Urothelial Carcinoma Patients Research Articles

Role of neoadjuvant chemotherapy in patients with locally advanced and clinically positive nodes Upper Tract Urothelial Carcinoma treated with Nephroureterectomy: real-world data from the ROBUUST 2.0 Registry.

To assess the impact of neoadjuvant and adjuvant chemotherapy on survival outcomes, within a large multicenter cohort of Upper tract urothelial carcinoma patients treated with Nephroureterectomy. A multicenter retrospective analysis utilizing the Robotic surgery for Upper Tract Urothelial Cancer Study registry was performed. Baseline, preoperative, perioperative, and pathologic variables of three groups of patients receiving surgery only, neoadjuvant or adjuvant chemotherapy were compared. Categorical and continuous variables among the three subgroups were compared with Chi square and ANOVA tests. The impact of perioperative chemotherapy on survival outcomes was assessed with the Kaplan Meier method. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival. Overall, 1,994 patients were included. Overall and Clavien grade ≥3 complications rates were comparable among the three subgroups (p = 0.65 and p = 0.92). At Kaplan Meier analysis, neoadjuvant chemotherapy significantly improved cancer-specific survival (p = 0.03) and overall survival (p = 0.03) probabilities of patients with cT ≥ 3 tumors and of those with positive cN (p = 0.03 and p = 0.02). On multivariable analysis, neoadjuvant chemotherapy was independently associated with an improvement of cancer-specific survival in cT ≥ 3 patients (HR 0.44; p = 0.04), and of both cancer-specific survival (HR 0.50; p = 0.03) and overall survival (HR 0.53; p = 0.02) probabilities in positive cN patients. This large multicenter retrospective analysis suggests significant survival benefit in Upper tract urothelial carcinoma patients with either locally advanced or clinically positive nodes disease receiving neoadjuvant chemotherapy. These findings can be regarded as "hypothesis generating", stimulating future trials focusing on such advanced stages.

Cathepsin C Promotes Tumorigenesis in Bladder Cancer by Activating the Wnt/β-catenin Signalling Pathway

Background: Cathepsin C (CTSC) participates in the development of numerous cancers; however, its function in bladder cancer (BCa) remains largely unknown. Methods: Bioinformatics prediction, quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay, and Western blot assay were used to determine CTSC expression in BCa tissues, paracancer tissues, BCa cells, and normal uroepithelial cells (SV-HUC-1). Colony formation, cell counting kit-8 (CCK-8), and Transwell assays were utilised to ascertain the involvement of CTSC in BCa. The effect of CTSC on BCa was further studied in vivo via animal experiments. Results: CTSC exhibited a heightened expression in BCa cells and tissues; meanwhile, bladder urothelial carcinoma (BLCA) patients with enhanced CTSC expression had a remarkably reduced overall survival than those with low CTSC expression. The overexpression of CTSC substantially enhanced the activity, proliferation, migration, and invasion of BCa cells, whereas its suppression repressed the above biological phenotypes. CTSC could activate the Wnt/β-catenin signalling pathway and upregulate diaphanous-related formin 3 (DIAPH3). CTSC overexpression combined with DIAPH3 knockdown partially reversed the impact of CTSC overexpression on the biological behaviour of BCa cells and the activation of the Wnt/β-catenin signalling pathway. Conclusions: CTSC was upregulated in tissues and BCa cells, and high CTSC expression was associated with poor overall survival. CTSC could enhance the activity, proliferation, migration, and invasion of BCa cells via upregulating DIAPH3 and activating the Wnt/β-catenin pathway.

2018P Nephron-sparing surgery combined with perioperative systemic therapy in select high-risk upper tract urothelial carcinoma (UTUC) Patients: A pilot study for a prospective phase II trial

2018P Nephron-sparing surgery combined with perioperative systemic therapy in select high-risk upper tract urothelial carcinoma (UTUC) Patients: A pilot study for a prospective phase II trial

1985P Retrospective database analysis of real-world treatment patterns and sequencing in locally advanced or metastatic urothelial carcinoma patients receiving sacituzumab govitecan

1985P Retrospective database analysis of real-world treatment patterns and sequencing in locally advanced or metastatic urothelial carcinoma patients receiving sacituzumab govitecan

Immune-Related Adverse Events of Genitourinary Cancer Patients, a Retrospective Cohort Study.

Immune checkpoint inhibitors (ICIs) have become common lines of therapy for genitourinary cancers (GUcs). Given their widespread use, understanding the risk factors, comparative profiles, and timing of immune-related adverse events (irAEs) is essential. We created an IRB-approved retrospective registry of all patients who received at least one dose of an ICI for any indication between 1 February 2011 and 7 April 2022 at a comprehensive cancer center and its outreach clinics. Dichotomous outcomes were modeled using multivariable logistic regression. Survival outcomes were compared using multivariable Cox regression. Among 3101 patients, 196 had renal cell carcinoma (RCC) and 170 had urothelial tumors. RCC patients were more likely to experience irAEs (OR 1.78; 95% CI 1.32-2.39), whereas urothelial carcinoma patients were not (OR 1.22; 95% CI 0.88-1.67). RCC patients were more prone to dermatitis, thyroiditis, acute kidney injury, and myocarditis, compared to other tumors, while urothelial carcinoma patients were not. The impact of irAEs on survival was not significantly different for GUcs compared to other tumors. RCC primaries have a significantly different irAE profile than most tumors, as opposed to urothelial primaries. Further, RCC was more likely to experience any irAEs. Heterogeneity of survival benefits by irAEs was not seen.

Immunohistochemical expression of GATA3, CK5/6 and CK20 in molecular subtypes of bladder carcinoma: correlation with clinicopathological features

BackgroundBladder urothelial carcinoma, is considered the 7th most common cancer in males. It is classified into luminal and basal subtypes depending on molecular markers, influencing prognosis and treatment. Identifying reliable biomarkers like GATA3, CK20, and CK5/6 through immunohistochemical methods can aid in early detection, risk stratification, and personalized treatment strategies. This study aims for evaluation prognostic role of these mentioned markers in correlation with clinicopathological parameters in urothelial carcinomas.MethodsTumor samples of forty cases were immunohistochemically stained for GATA3, CK5/6, and CK20. A cutoff of 20% positivity was used to determine subtype classifications, with staining patterns guiding the categorization into basal, luminal, double positive, or double negative groups.ResultsIn this study of 40 urothelial carcinoma patients tumors were classified into basal and luminal subtypes using GATA3, CK5/6 and CK20 markers. GATA3 expression showed no significant association with clinicopathological parameters; while, CK20 was associated with tumor size, and CK5/6 with T, N classification, and lymphovascular invasion. Significant differences in clinicopathological parameters were observed when subtypes were defined by CK5/6, GATA3 or CK20, particularly in tumor grade, T and N classification, and gender. Basal molecular subtypes was correlated with poor prognostic parameters.ConclusionsThis study documented that use of triple markers could define the luminal and basal subtypes of urothelial carcinoma. Basal tumors have shown to be associated with the aggressive behavior and future studies may allow the development of new therapies in the context of molecular subtypes.

Central pathology review and its prognostic value in upper tract urothelial carcinoma patients: a nationwide multi-institutional study

The prognostic value of central pathology review in upper urinary tract cancer (UTUC) remains inadequately addressed in existing literature. In this study, we conducted an extensive central pathology review and presented its influence on multi-center UTUC studies. We conducted a retrospective review of patients who underwent radical nephroureterectomy or segmental resection for UTUC to determine eligibility for central pathology review. In the Taiwan UTUC Collaboration cohort, 377 cases met the criteria for pathology review. We assessed agreement between pathologists using both the total percentage of agreement and simple kappa statistics. The prognostic implications of original and review pathology for various parameters were examined using the Cox regression model. This study included 209 female and 168 male participants. Pathology review revealed substantial interobserver variability in pT staging, with a particularly high rate of pT2 cases being upgraded to pT3 upon central review (17/70 pT2 stage made by local pathologists were finally confirmed as pT3 disease by the review pathologist). The local pathologist cohort identified fewer significant histological predictors in survival models compared to the review pathology cohort. Advanced pT stage, perineural invasion (PNI), and positive surgical margin were independent predictors of poorer overall survival and cancer-specific survival. PNI, lymphatic vascular invasion, and positive surgical margin were independent predictors of disease recurrence. Substantial interobserver variability in histological assessment underscores the importance of centralized pathology review for both multi-center studies and accurate post-operative management of UTUC patients. Advanced stage, perineural invasion, and margin status were significant histological predictors of oncological outcomes.

Race/Ethnicity Affects Access and Survival Differences After Neoadjuvant or Adjuvant Chemotherapy at Radical Cystectomy in Urothelial Carcinoma Patients.

It is unknown whether race/ethnicity affects access and/or survival after neoadjuvant (NAC) or adjuvant chemotherapy (ADJ) at radical cystectomy (RC). We addressed these knowledge gaps. Within the Surveillance, Epidemiology, and End Results database (2007-2020), we identified NAC candidates (T2-T4N0M0) and ADJ candidates (T3-T4 and/or N1-3). We focused on the four most prevalent race/ethnicities: Caucasians, Hispanics, African American (AA), and Asian/Pacific Islanders (API). Multivariable logistic regression models (MLR) tested access to NAC and ADJ. Subsequently, within NAC-exposed patients, survival analyses consisting of Kaplan-Meier plots and multivariable Cox regression models addressed CSM according to race/ethnicity were fitted. We repeated the same methodology in ADJ-exposed patients. In 6418 NAC candidates, NAC was administered in 1011 (19.0%) Caucasians, 88 (21.0%) Hispanics, 65 (17.0%) AA, and 53 (18.0%) API. In MLR, AA exhibited lower access rates to NAC (OR 0.83, p = 0.04). In NAC-exposed patients, AA independently predicted higher CSM (HR 1.3, p < 0.001) and API independently predicted lower CSM (HR 0.83, p = 0.03). Similarly, in 5195 ADJ candidates, ADJ was administered to 1387 (33.0%) Caucasians, 100 (28.0%) Hispanics, 105 (29.0%) AA, and 90 (37.0%) API. In MLR, AA (OR 68, p = 0.003) and Hispanics (OR 0.69, p = 0.004) exhibited lower access rates to ADJ. In ADJ-exposed patients, AA independently predicted lower CSM (HR 1.32, p < 0.001), while API showed better CSM (HR 0.82, p = 0.01). Relative to Caucasians, AA are less likely to receive either NAC or ADJ. Moreover, relative to Caucasians, AA exhibit higher CSM even when treated with either NAC or ADJ.

Exploring Radiotherapy as a Promising Alternative for Managing Advanced Upper Tract Urothelial Carcinoma: Rescuing Chemotherapy-Intolerant Patients

PurposeTo investigate the safety and effectiveness of radiotherapy for advanced upper tract urothelial carcinoma (UTUC) patients intolerant to chemotherapy. MethodsData for 21 patients with advanced UTUC intolerant to chemotherapy were retrospectively collected. All patients were treated with conventionally fractionated radiotherapy (50-70 Gy/20-33 f) or partial-SABR boost to the lesions (50-60 Gy/20-25 f with tumor center boosted with 6-8 Gy/f, 3-5 f) for bulky tumors. ResultsThe median age was 75 years (range, 58-87 years). Primary tumor resection was performed for all patients and none underwent metastatic resection. Seventeen (81%) patients had oligometastasis (1-5 metastases) at diagnosis. Eighteen (85.7%) received irradiation to all tumor lesions. Lymph node metastasis was predominant in the whole group (17/21). Other lesions were distributed as local recurrence (7/21), bone metastases (2/21) and abdominal wall/muscle (2/21). The median follow-up time was 38.5 months (interquartile range, 15.2-48.7 months). Rate of local control (LC), progression-free survival (PFS) and overall survival (OS) of the whole group at 1 year were 90%, 46.6%, and 80.4%, respectively. At 3 years, LC, PFS and OS were 65.6%, 26.6%, and 40.9%, respectively. Fourteen patients developed acute mild gastrointestinal toxicity, generally of grade 1-2; 8 patients developed acute grade 1-2 hematological toxicity, consisting mainly of anemia and leukopenia. No grade 3 or higher acute or late toxicities were observed. ConclusionFor patients with advanced UTUC who are not able to tolerate chemotherapy, radiotherapy is a safe treatment and can achieve good local tumor control.

Lab-in-a-Vial Rapid Test for Internet of Things-Embedded Point-of-Healthcare Protein Biomarker Detection in Bodily Fluids.

Amateurs often struggle with detecting and quantifying protein biomarkers in body fluids due to the high expertise required. This study introduces a Lab-in-a-Vial (LV) rapid diagnostic platform, featuring hydrangea-like platinum nanozymes (PtNH), for rapid, accurate detection and quantification of protein biomarkers on-site within 15min. This method significantly enhances detection sensitivity for various biomarkers in body fluids, surpassing traditional methods such as enzyme-linked immunosorbent assays (ELISA) and lateral flow assays (LFA) by ≈250 to 1300 times. The LV platform uses a glass vial coated with specific bioreceptors such as antigens or antibodies, enabling rapid in vitro evaluation of disease risk from small fluid samples, similar to a personal ELISA-like point-of-care test (POCT). It overcomes challenges in on-site biomarker detection, allowing both detection and quantification through a portable wireless spectrometer for healthcare internet of things (H-IoT). The platform's effectiveness and adaptability are confirmed using IgG/IgM antibodies from SARS-CoV-2 infected patients and nuclear matrix protein (NMP22) from urothelial carcinoma (UC) patients as biomarkers. These tests demonstrated its accuracy and flexibility. This approach offers vast potential for diverse disease applications, provided that the relevant protein biomarkers in bodily fluids are identified.

Pembrolizumab in Patients with Advanced Urothelial Carcinoma with ECOG Performance Status 2: A Real-World Study from the ARON-2 Project.

The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown. In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2. Patients aged ≥18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2. We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5-16.1) in the overall study population, 18.2 months (95% CI 15.8-22.2) in patients with ECOG-PS 0-1, and 3.7 months (95% CI 3.2-5.2) in subjects with ECOG-PS 2 (p<0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3-97.1), 6.2 months (95% CI 5.5-97.1) in patients with ECOG-PS 0-1, and 2.8 months (95% CI 2.1-3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy. This large real-world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice.

Arsenic-induced disruption of circadian rhythms and glutamine anaplerosis in human urothelial carcinoma

Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH: quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.

Enfortumab Vedotin for Elderly Advanced Urothelial Carcinoma Patients or Those With a Poor Performance Status.

The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear. We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023. Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001). EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated.

Objective Response Rate is a Surrogate Marker for Long-Term Overall Survival in Metastatic Urothelial Carcinoma Patients Treated With Immune Checkpoint Inhibitors

BackgroundThis study aimed to evaluate the utility of RECIST criteria-based objective response rate (ORR) as a potential surrogate endpoint for long-term overall survival (OS) in patients with metastatic urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs). MethodsThe primary endpoint was overall ORR and OS, duration of treatment (DoR) with ICIs. ORR was analyzed using Fisher's exact test. Median follow-up and OS were estimated by using the Kaplan–Meier method. ResultsThe median follow-up was 58 (1.15-71) months. Progression developed in 94 (47%) patients during the first 3 months of ICIs therapy. The treatment response to ICIs included complete response (CR), partial response (PR) and stable disease in 10% (n = 20), 23% (n = 46), and 20% (n = 41) of patients, respectively. The responder and nonresponder groups differed in terms of certain baseline characteristics, such as Bellmunt risk factors, and neutrophil-to-lymphocyte ratio (NLR). The 5-year OS rates for patients with CR and PR were 73% and 23%, respectively. The median DoR for CR, PR, and SD were 51.8 months (44.5-59.1), 20.7 months (16.7-24.6), and 8.8 months (5.5-12.1), respectively. Overall, 16(80%) patients with CR and 14(30%) patients with PR had an ongoing response at the time of the analysis. In the univariate analysis, NLR > 3, liver metastases, ECOG PS ≥ 1, and hemoglobin levels < 10 mg/dl, as well as the PR and CR, were all significantly associated with OS. In multivariate analysis, presence of liver metastases (HR 2.3; 95% CI, 1.3-4.2; P < .004) was found to be an independent determinant of short OS, while PR (HR 0.3; 95% CI, 0.15-0.5; P < .001) and CR (HR 0.06; 95% CI, 0.014-0.27; P < .001) were associated with improved OS. ConclusionsIn conclusion, this 5-year analysis of real-world data in the setting of metastatic urothelial cancer indicated a significant correlation between ORR, especially CR, and OS in patients who received ICIs. Therefore, identifying a potential surrogate marker for survival in patients treated with ICIs would represent an important advance in the early identification of patients’ response or resistance to ICIs.

Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations.

In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1. There have been no reports of the Japanese subgroup results yet. THOR Cohort 1 randomized patients to erdafitinib once daily or docetaxel/vinflunine once every 3weeks. Primary endpoint was OS. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). No specific statistical power was set for this Japanese subgroup analysis. Of 266 patients randomized, 27 (14 erdafitinib; 13 chemotherapy) were Japanese. Baseline characteristics were generally similar between treatments and to the overall population, except for more males, lower body weight, and more upper tract primary tumors among Japanese patients. Compared with chemotherapy, erdafitinib showed improved OS (median 25.4 versus 12.4 months), PFS (median 8.4 versus 2.9months) and ORR (57.1% versus 15.4%). Any grade treatment-related adverse events (AEs) occurred in all patients from both arms but Grade 3/4 AEs and AEs leading to discontinuation were lower in the erdafitinib arm. No new safety signals were observed in the Japanese subgroup. In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered.

Antibiotic use attenuates response to immune checkpoint blockade in urothelial carcinoma via inhibiting CD74-MIF/COPA: revealing cross-talk between anti-bacterial immunity and anti-tumor immunity through a tumor marker prognostic study.

Immune checkpoint blockade (ICB) has emerged as a promising therapy for both resectable urothelial carcinoma (UC) patients preparing for radical surgery and unresectable UC patients, whereas the objective response rate of ICB remains unsatisfactory due to various factors. Antibiotic (ATB) use can influence intra-tumoral bacteria, which may further reduce ICB efficacy. The study aims to evaluate the effects of ATB use on prognosis and response in UC patients undergoing ICB, and explore potential molecular mechanisms of ATBs and intra-tumoral bacteria impacting UC immune microenvironment. Pooled analyses, synthesizing evidence from 12 studies and 3496 UC patients with ICB treatment, was conducted via a meta-analysis. In addition, single-cell RNA and single-cell microbiome data were analyzed based on eight UC samples and 63185 single cells. Bulk RNA sequencing and clinical data from a single-arm, multi-center, atezolizumab-treated, phase 2 trial, IMvigor210, were used for validation. The study is registered at PROSPERO (XXX) and at Research Registry (XXX). ATB use exhibited worse overall survival (HR=1.46, 95%CI=[1.20, 1.77], P<0.001, heterogeneity I²=51%) and lower objective response (OR=0.43, 95%CI=[0.27, 0.68], P<0.001, heterogeneity I²=0%) in UC patients receiving ICB. Single-cell transcriptome and single-cell microbiome analyses identified the presence of intra-tumoral bacteria was obviously related to elevated anti-bacterial immune functions; and anti-bacterial immunity was positively correlated to anti-tumor immunity in UC immune microenvironment. Intra-tumoral bacteria could up-regulate CD74-MIF/COPA signaling of immune cells and activation of CD74-MIF/COPA mediated the promotion of T cell anti-tumor function induced by anti-bacterial immune cells. UC patients with higher CD74-MIF/COPA signaling carried better overall survival (HR=1.60, 95%CI=[1.19, 2.15], P=0.002) in IMvigor210 immunotherapy cohort. ATB use reduces overall survival and objective response to ICB in UC patients. Anti-bacterial immune cell functions induced by intra-cellular bacteria in UC microenvironment might up-regulate the function of anti-tumor T immune cells via activating CD74-MIF/COPA, whereas ATB could inhibit the above process through killing intra-cellular bacteria and result in poorer clinical benefit of ICB. The use of ATB should be considered carefully during neoadjuvant immunotherapy period for resectable UC patients preparing for radical surgery and during immunotherapy period for unresectable UC patients.

Efficacy of trametinib in a metastatic urothelial carcinoma patient with a BRAF mutation

IntroductionBRAF mutations in bladder cancer are rare. MEK inhibitors have excellent clinical benefits in the treatment of melanoma.Case presentationA 60‐year‐old male was diagnosed with muscle‐invasive bladder cancer and underwent total cystectomy and ileal conduit diversion. Despite 4 cycles of gemcitabine and cisplatin chemotherapy and 3 courses of pembrolizumab, the left obturator lymph node enlarged. Cancer multi‐gene panel testing confirmed the BRAF G469A mutation and trametinib was recommended. Three months after the initiation of trametinib (2 mg, qd), the left obturator lymph node shrank by more than 50%. The disease has remained stable for more than 18 months.ConclusionThe present case indicates the potential of trametinib to treat mBUC patients with the BRAF G469A mutation in this setting.

Association between response to enfortumab vedotin and peripheral neuropathy in urothelial carcinoma patients: a multicenter retrospective study

Abstract Background Enfortumab vedotin (EV) was approved for patients with metastatic urothelial carcinoma (mUC) who progressed after anticancer therapy on September 2021 in Japan. The association between the occurrence of EV-related side effects and clinical outcome remains to be elucidated. Methods We identified 97 mUC patients treated with EV therapy at our five institutions from the date of approval to March 2023. The median follow-up period was 7.0 months. We retrospectively analyzed the efficacy and safety of EV. Results The median age of the patients was 71 years old, 39% had PS of 1 or more, and 56.7% had primary tumor in upper urinary tract. Overall response rate (ORR) to EV therapy, median progression-free survival (PFS), and overall survival (OS) were 43.3%, 7.52 months, and 12.78 months, respectively. Any grade of treatment-related skin disorder, dysgeusia, peripheral neuropathy, gastrointestinal disorder, and hyperglycemia occurred in 61 (62.9%), 36 (37.1%), 34 (35.1%), 29 (29.9%), and 18 (18.6%) patients, respectively. The patients with EV-associated peripheral neuropathy had significantly higher ORR (58.8% vs. 34.9%, P = .032) and longer median PFS (8.05 vs. 6.31 months, P = .017) and OS (not reached vs. 11.57 months, P = .008, respectively) than those without. The occurrence of peripheral neuropathy after EV treatment and the presence of peritoneal dissemination were factors independently associated with PFS (hazard ratio = 0.46, P = .008 and hazard raito = 3.83, P = .004, respectively) and OS (hazard ratio = 0.30, P = .005 and hazard raito = 4.53, P = .002, respectively). Conclusions The occurrence of EV-related peripheral neuropathy might be associated with the efficacy of EV therapy in mUC patients.

Using machine learning to develop preoperative model for lymph node metastasis in patients with bladder urothelial carcinoma

BackgroundLymph node metastasis (LNM) is associated with worse prognosis in bladder urothelial carcinoma (BUC) patients. This study aimed to develop and validate machine learning (ML) models to preoperatively predict LNM in BUC patients treated with radical cystectomy (RC).MethodsWe retrospectively collected demographic, pathological, imaging, and laboratory information of BUC patients who underwent RC and bilateral lymphadenectomy in our institution. Patients were randomly categorized into training set and testing set. Five ML algorithms were utilized to establish prediction models. The performance of each model was assessed by the area under the receiver operating characteristic curve (AUC) and accuracy. Finally, we calculated the corresponding variable coefficients based on the optimal model to reveal the contribution of each variable to LNM.ResultsA total of 524 and 131 BUC patients were finally enrolled into training set and testing set, respectively. We identified that the support vector machine (SVM) model had the best prediction ability with an AUC of 0.934 (95% confidence interval [CI]: 0.903–0.964) and accuracy of 0.916 in the training set, and an AUC of 0.855 (95%CI: 0.777–0.933) and accuracy of 0.809 in the testing set. The SVM model contained 14 predictors, and positive lymph node in imaging contributed the most to the prediction of LNM in BUC patients.ConclusionsWe developed and validated the ML models to preoperatively predict LNM in BUC patients treated with RC, and identified that the SVM model with 14 variables had the best performance and high levels of clinical applicability.

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10–50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.