bluuebunny/crossref_metadata_2025 huggingface dataset:
Enfortumab vedotin-related skin toxicities in patients with urothelial carcinoma: A systematic review and meta-analysis.
Authors: Gazzoni Gabriela , Vilbert Maysa , Oliveira João Pedro , Dacoregio Maria Inez , Michelon Isabella , Reis Pedro , Braga Marcelo , Simões Clara , Oliveira Lilia , Cardoso Ana Paula Garcia
Published: February 2025

761

Background:
Enfortumab vedotin (EV) is an antibody-drug conjugate that binds nectin-4, a cell-adhesion molecule highly expressed in urothelial carcinoma (UC) and epidermal keratinocytes. Dermatologic events have become important EV-related toxicities in clinical trials (CT) and observational studies. We conducted a systematic review and meta-analysis on skin toxicity in UC patients treated with EV.
Methods:
We systematically searched Pubmed, Cochrane, and Embase for published CT and observational studies reporting EV-related skin toxicities in UC patients. We investigated treatment-related adverse events (TRAE) and severe cutaneous adverse reactions (SCAR) in UC patients of all-grade and ≥ 3. The outcomes were presented as overall incidence rates and 95% confidence intervals (95% CI). Statistical analyses were performed using R software.
Results:
Ten studies comprising 1,061 participants were included. Median age ranged from 66 to 76 years, and 74% (783) were male. 72% of patients had prior immune checkpoint inhibitors. The median time to onset of skin toxicity varied from two to four weeks. In a pooled analysis, the skin reaction rate for all-grade of UC was 50% (95% CI 38-61), while for grade ≥ 3 was 10% (95% CI 7-15). The incidence of SCAR was 19% (95% CI 16-23) and 8% (95% CI 3-18) for grade ≥ 3. Alopecia was seen in 37% of patients, pruritus in 22% and dry skin in 21%. All-grade rash incidence rate was 29% and the most reported was maculopapular rash 22%, followed by erythematous rash (6%). Important cutaneous reactions included bullous dermatitis in 2.91% of patients (95% CI 1-6), palmar-plantar erythrodysesthesia in 2.46% (95% CI 1-5), Stevens-Johnson syndrome in 1.46% (95% CI 0.4-5), and toxic epidermal necrolysis in 0.95% (95% CI 0.2-4) of patients.
Conclusions:
This is the first study to characterize EV-related dermatological toxicities. We found a high incidence of all-grade events and a moderate frequency of severe and grade ≥ 3 toxicities. This study intends to highlight the need for close monitoring and adequate treatment for skin toxicities in UC patients receiving EV.
Differences in health-related quality of life between rural and urban bladder cancer patients following radical cystectomy.
Authors: Westhofen Thilo , Buchner Alexander , Schulz Gerald Bastian , Eismann Lennert , Rodler Severin , Berg Elena , Aydogdu Can , Askari Darjusch , Becker Armin , Stief Christian G. , Kretschmer Alexander
Published: February 2025

766

Background:
Bladder cancer (BC) patients from rural areas (RA) may have more difficult access to health care with potentially detrimental impact on oncological outcome following radical cystectomy (RC). However, little is known on differences in health-related quality of life (HRQOL) between rural- and urban residents treated with RC for BC. We therefore aimed to assess these differences between rural and urban BC-patients by providing HRQOL data from a large prospective cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs.
Methods:
n=1514 consecutive patients [n=576 from urban areas (UA), n=938 from rural areas (RA)] who underwent RC at a large tertiary care center were included. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was assessed preoperatively, at 3 months, then annually until a maximum follow-up of 120 months, applying the validated EORTC QLQ-C30- as well as the bladder cancer-specific QLQ-BLM30- and FACT-BL-questionnaires. Separate modeling of longitudinal HRQOL for rural- and urban patients was performed. Spearman’s rank correlation was applied to identify residential-specific factors influencing HRQOL.
Results:
At baseline rural- and urban residents showed no significant difference in general HRQOL assessed by the global health status domain (GHS) (p=.983). In line no differences regarding symptom-related subscales were observed between both cohorts (p-range: .189 - .907). Postoperatively and in longitudinal analysis, rural residents reported significantly better general HRQOL up to 96 months after RC (p-range: .001 - .037). At 12 months, a significant correlation between physical-, emotional functioning or urinary continence and better general HRQOL was observed for both, rural- and urban residents (each p< .001). No significant correlation was found between sexual functioning and increased general HRQOL. While a significant correlation between Social/Family wellbeing and increased general HRQOL was found for rural residents (p=.042), no correlation was found for urban residents (p=.594).
Conclusions:
The current study provides prospective data from a contemporary cohort of BC-patients, which display residential-specific differences in the natural course of HRQOL following RC. Those results are important to guide individualized treatment decision-making for patients with BC.
PUNCH01: Interim results from a phase II study of intra-arterial chemotherapy (IAC) combined with tislelizumab and bacillus Calmette-Guerin (BCG) in high-risk non-muscle-invasive bladder cancer (HR NMIBC).
Authors: Wang Zongren , Huang Bin , Luo Cheng , Wu Yuxi , Lei Jiahao , Chen Lingwu , Chen Junxing
Published: February 2025

767

Background:
Our study was established to evaluate the efficacy and safety of IAC combined with tislelizumab and BCG as a bladder-preserving treatment for HR NMIBC pts.
Methods:
This open-label, single arm phase II study enrolled BCG-naïve HR NMIBC pts with papillary tumors (high-grade Ta or T1 tumors). Firstly, the papillary tumors should be removed all visible lesions by TURBT. Secondly, angiographic catheter was placed into the internal iliac arteries with Seldinger’s percutaneous technique, cisplatin (60 mg/m
2
) and epirubicin (50 mg/m
2
) were administered arterially in day 1 (D1), every 3 weeks for 2-4 cycles. And pts received tislelizumab 200 mg ivgtt in D1, every 3 weeks for 2-4 cycles. Finally, pts received 18 instillations of BCG plus at least 8 cycles of tislelizumab (200 mg ivgtt, every 3 weeks). Specifically, pts were started on an induction course of BCG with 6 instillations every week, followed by maintenance with 3 instillations every 2 weeks and 9 instillations every 4 weeks. The primary end point was disease-free survival(DFS) rate at 12 months. Secondary end points were bladder-preservation rate, OS and safety. Our study estimated a DFS rate at 12 months was no less than 55% and the study would enroll 29 pts.
Results:
By Jul. 2024, 23 eligible pts were enrolled. Twenty-two pts were analyzed (male 90.9%; median age 61 years(37-80); pure TCC 80.0%; median tumor size 3.0 cm (0.4-8.0); multiple papillary tumours=72.7%; high-gradeTa=54.5%, T1=45.5%). Median follow-up was 11.4 months (6.0-40.3), the mean number of IAC cycles was 2.7, mean number of tislelizumab cycles was 8.3, and the median BCG instillations was 10 (6-18). The DFS rate at 12month was 100.0% (95%CI, 63.8%-100%). The bladder-preservation rate at 12 months was 100% (95%CI,100%-100%). The OS rate at 12 months was 100% (95%CI, 100%-100%). 18 pts experienced treatment related adverse events, including nausea (n=6, G2), neutropenia (n=4, G2), fatigue (n=3, G2), increased AST/ALT (n=3,G2), fever (n=2, G3) and myalgia (n=1, G2).
Conclusions:
Our interim results supported the use of IAC combined with tislelizumab and BCG as a promising bladder-preserving strategy for HR NMIBC pts. Clinical trial information:
ChiCTR2200067156
.
Neuropathy, skin rash, and hyperglycemia as predictors of response to enfortumab vedotin in locally advanced and metastatic bladder and upper tract urothelial carcinoma.
Authors: Salous Tareq , Hassoun Rebecca , Althouse Sandra K. , Schneck Stephanie , King Jennifer , Adra Nabil
Published: February 2025

771

Background:
Enfortumab vedotin (EV) in combination with pembrolizumab is FDA approved for treatment of locally advanced and metastatic urothelial cancer. Neuropathy, skin rash, and hyperglycemia are common side effects of EV. We evaluated the impact of presence of neuropathy, skin rash, and hyperglycemia on progression free survival (PFS) in patients (pts) with bladder or upper tract urothelial carcinoma treated with EV.
Methods:
The Indiana University bladder cancer database was queried for pts with locally advanced and metastatic bladder and upper tract urothelial carcinoma who were treated with EV with or without pembrolizumab. Pts with variant histology were included. Toxicities were documented throughout the course of treatment. Association of neuropathy, skin rash and hyperglycemia and PFS were compared to patients without any of the side effects using the log-rank test.
Results:
Between 2018-2024, a total of 83 pts were treated with EV with at least 2 doses. The median age was 69 years (range, 39-89). 47 pts had EV + pembrolizumab, while 36 pts had EV as single agent. 43 pts received EV as 1st, 28 pts as 2nd, 10 pts as 3rd, and 2 pts as 4th line of treatment. Metastatic sites were lymph nodes in 42 pts, lungs in 34 pts, bones in 29 pts, liver in 16 pts, and brain in 7 pts. Median follow-up from the start of EV treatment was 14 months (range, 1-33). Neuropathy was reported in 30 (36%) pts, skin rash in 32 (39%) pts, and hyperglycemia in 6 (7%) pts. The median PFS in patients who did not experience neuropathy/skin rash/hyperglycemia was 4.5 months (95% CI, 2.4-11.0), 10.6 months (95% CI, 7.2-15.7) in pts who experienced neuropathy (P = 0,01), 8.6 months (95% CI, 7.3-20.2) in pts who experienced skin rash (P = 0.01), and 15.9 months (95% CI, 5.1-15.9) in pts who experienced hyperglycemia (P = 0.03).
Conclusions:
The presence of neuropathy, skin rash, or hyperglycemia in patients with metastatic bladder or upper tract urothelial carcinoma treated with EV was associated with improved PFS.
The role of salvage cystectomy after prior trimodality therapy.
Authors: Pyrgidis Nikolaos , Schulz Gerald Bastian , Schilipoti Pietro , Pellegrino Francesco , Casuscelli Jozefina , Tzelves Lazaros , Ciavarella Davide , Mir Maria del Carmen , Klatte Tobias , Belinchon Ramos , Velasco Jorge Caño , Fujii Yasuhisa , Tanaka Hajime , Yoshida Soichiro , Umari Paolo , Teoh Jeremy Y.C. , Ming Chris Wong Ho , Simone Giuseppe , Mastroianni Riccardo , Moschini Marco
Published: February 2025

781

Background:
Trimodality therapy (TMT) with transurethral resection followed by radiation of the urinary bladder and chemotherapy is associated with similar long-term survival rates compared to radical cystectomy (RC) for well-selected patients. Nevertheless, salvage RC may become necessary in 10% of patients receiving TMT. We aimed to assess the perioperative and long-term outcomes of salvage RC after prior TMT through a large multinational cohort study.
Methods:
We included patients with pure urothelial cancer of the urinary bladder. Patients undergoing salvage RC after prior TMT due to recurrence in the urinary bladder from 11 high-volume centers were matched with a propensity score matching on a 1:1 ratio with patients without prior TMT undergoing primary RC. The two groups were adjusted for institution, age, histological status, ASA score, and surgical technique.
Results:
We included 108 patients (54 per group) with a median age of 74 years (IQR: 66-78). The two groups did not differ in terms of operative time (TMT: 250 versus non-TMT: 251 minutes, p = 0.9), intraoperative blood loss (TMT: 550ml versus non-TMT: 600ml, p = 0.2), and perioperative Clavien-Dindo complications (p = 0.9). At a follow-up of 16 months (IQR: 6-38), 45 (42%) deaths occurred. Prior TMT was associated with higher mortality rates in the survival analysis (log-rank test: p = 0.037). Accordingly, the progression rates were higher in patients with prior TMT (log-rank test: p = 0.047).
Conclusions:
Salvage RC after TMT is associated with similar perioperative outcomes compared to primary RC. Nevertheless, patients undergoing salvage RC after TMT may present worse progression rates and overall survival in the long term. Therefore, systemic therapies should be considered in patients with recurrence after TMT.
Efficacy and safety of fexagratinib (Fexa) in combination with tislelizumab (T) in a phase II study of patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC) harboring FGFR alterations (FGFRa).
Authors: Bian Xiaojie , Ye Dingwei , Chen Lijun , Hu Changlu , Jiang Shusuan , Xing Nianzeng , Zhang Qingyun , Zhang Shuang , Chen Jimin , Cheng Fan , Li Guiling , Hu Bin , Wang Gongxian , Niu Haitao , Chen Hui , Yang Jinjian , Zhang Peng , Yuan Quan , Gu Xi , Chen Yichao
Published: February 2025

789

Background:
A significant proportion of pts with mUC are intolerant to platinum-based chemotherapy, highlighting the urgent need for alternatives. Fexagratinib(former AZD4547)is a potent and selective inhibitor of FGFR and had showed promising anti-tumor activity in mUC pts with FGFRa. This Phase II study (NCT05775874) aimed to evaluate efficacy of Fexa plus T combination treatment (Tx) in mUC pts harboring FGFRa who were 1st-line platinum-ineligible or rejected chemotherapy.
Methods:
FGFR3 mRNA overexpression were detected by in situ hybridization (RNAscope). FGFR3 activating mutations or fusions were detected by NGS. Eligible pts received continuous oral Fexa 80mg BID plus T 200 mg infusion on day 1 of a 21-day cycle. Primary objectives were objective response rate (ORR) by Independent Review Committee (IRC) per RECIST 1.1.
Results:
As of data cut off (10 Aug 2024), 26 pts received combination Tx with the majority being treatment-naïve. Of those, 57.7% were male with median age of 68.5 years and 86% had an ECOG of 1. Nine pts had confirmed FGFR3 mutation or fusion and 24 pts were overexpression. In 22 pts with available PD-L1 expression status, 86.4% were negative (CPS<10). Among 24 IRC evaluable pts, 9 (37.5%) partial responses (PRs) were confirmed. The median duration of response was 5.9 months. The median progression free survival mPFS was 5.3 months (95%CI 2.7-8.2) with 4 pts were still on Tx. Among the evaluable pts with FGFR3 overexpression but without mutation/fusion, ORR was37.5%,(6/16)pts.Most common treatment-related adverse events (TRAEs) were stomatitis (42%), anemia (38.5%), AST/ALT increased (27%). Grade ≥3 TRAEs occurred in 12 (46.2%) pts, incidence >10% events included stomatitis (n=3, 12%), hand-foot syndrome(n=3, 12%). Immune-related AEs occurred in 23.0% of pts. The majority of TRAEs were reversible.
Conclusions:
1st-line Tx with Fexa plus T were tolerable with a safety profile consistent with previously reported for both agents. The toxicity was overall manageable. Encouraging efficacy was observed in pts with FGFR3 overexpression, regardless of PD-L1 expression or FGFR3 mutations/fusions.Further exploration of these findings is warranted. Clinical trial information:
NCT05775874
.
Efficacy and safety of fexagratinib (Fexa) in Chinese patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) harboring FGF receptor (FGFR) genetic alterations.
Authors: Bian Xiaojie , Wang Shanshan , Ye Dingwei , Zhu Shaoxing , Gou Xin , Shi Benkang , Xiao Jun , Hu Bin , Liu Xianling , Jiang Shusuan , Liu Haitao , He Chaohong , Zhang Xiaoping , Chen Zhiwen , Kang Xinli , Li Changfu , Xu Ning , Yang Yong , Li Kun , Wang Qilin
Published: February 2025

790

Background:
Fexagratinib (former AZD4547), a selective and potent oral inhibitor of FGFR1-3, has shown promising efficacy and safety in phase I trials among solid tumor pts with FGFR1-3 alterations, including mUC. This study (NCT05086666) aimed to assess efficacy and safety of Fexa in previously treated Chinese mUC pts with FGFR alterations.
Methods:
Pts with mUC harboring FGFR3 alterations (including activating mutations or fusion detected via NGS panel) who failed at least 1 prior therapy or were platinum- ineligible, were enrolled. Pts received continuous oral Fexa 80mg BID until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per RECIST v1.1.
Results:
As of data cutoff (14 Jun 2024), a total of 35 pts were enrolled, of those 80% were male with a median age of 66 years (range 41-86). Most pts (85.7%) had ECOG PS≤1, 43% had a creatinine clearance <60 mL/min, 66% had received ≥ 1 prior therapies, 66% had been treated with PD-(L)1. The primary tumor site was reported in the upper tract in 40% of pts, and 25.7% had liver metastases. The best overall responses assessed by IRC was 34.4% (95% CI, 18.6%-53.2%) in 32 evaluable pts, including 9 confirmed partial responses (cPRs), 2 unconfirmed PRs. Ten (37.0%) of 27 evaluable pts harboring FGFR3 mutation achieved at least one PR. Among 15 pts who experienced progression after PD-(L)1 treatment, 5 pts (33.3%) achieved cPRs. Median PFS by IRC was 3.6 (2.8, 6.1) months. Most common treatment-related adverse events (TRAEs) were anemia (40.0%), nail disorder (40.0%), hyperphosphatemia (37.1%) and hyponatremia (34.3%). Grade ≥3 TRAEs were reported in 54.3% of the pts, incidence >5% included pneumonia(5.7%), anemia (5.7%) and hand-foot syndrome (5.7%).
Conclusions:
Fexa was generally well tolerated in previously treated Chinese mUC pts, with no new safety signals identified. The efficacy observed was consistent with that previously reported in western populations, with notable benefits seen in pts with FGFR alterations who had experienced disease progression following PD-(L)1 treatment. Clinical trial information:
NCT05086666
.
Comprehensive modalities of kidney-sparing treatment in a carefully selected cohort of localized high-risk upper tract urothelial carcinoma: A potential paradigm shift.
Authors: Chen Zeyu , Ye Jianjun , Tu Xiang , Liao Xinyang , Wang Qihao , Zheng Lei , Chen Kai , Wei Qiang , Bao Yige
Published: February 2025

794

Background:
This study aims to assess the efficacy and safety of comprehensive modalities of kidney-sparing treatment in a carefully selected cohort of patients with localized high-risk upper tract urothelial carcinoma (UTUC).
Methods:
This study was initiated in January 2019 and is ongoing. Selected localized high-risk UTUC patients, characterized by conditions such as solitary kidney, bilateral tumors, impending renal insufficiency or patient refusal/ineligibility for radical nephroureterectomy (RNU), were included. Systemic therapy regimens were tailored to patient characteristics, tumor pathology and biomarkers, and included platinum-based chemotherapy, Disitamab Vedotin, and immune checkpoint inhibitors (ICIs). After endoscopic biopsy and attempted laser ablation, patients received four cycles of systemic induction therapy, followed by maximal endoscopic laser ablation or segmental ureterectomy. Postoperatively, a one-year course of immunotherapy maintenance was administered. The co-primary endpoints were disease-free survival (DFS) and conversion-free survival (CFS). Secondary endpoints included metastasis-free survival (MFS), renal function changes, ureteral stricture and treatment safety.
Results:
68 patients were enrolled, with a follow-up of 18 months. 54 patients underwent endoscopic thulium laser tumor ablation, while 14 underwent segmental ureterectomy. The induction therapy comprised Disitamab Vedotin for 32 patients, platinum-based chemotherapy for 9, and immunotherapy for 37. Urothelial tract recurrence was observed in 28 patients with a 1-yr DFS rate was 58.82%, who subsequently underwent repeat endoscopic laser ablation. Salvage RNU was performed in 9 patients, yielding a 1-yr CFS rate of 93.7% and a 2-yr CFS rate of 88.9%. No distal metastasis was reported. Postoperative renal function impairment was noted in 15 patients (22.06%). Mean eGFR improvements were observed at various time points: 3.15 ml/min/1.73m
2
at 1 months, 5.07 ml/min/1.73m
2
at 3 months, 2.41 ml/min/1.73m
2
at 6 months, and 3.97 ml/min/1.73m
2
at 12 months. Ureteral stricture on the affected side was a common complication, which was more likely to occur in patients who underwent 3 or more times of ureteroscopy (9/27). Notably, no grade 3 or higher systemic toxicities were observed.
Conclusions:
Preliminary findings indicate that our comprehensive modalities of kidney-sparing treatment demonstrated promising tumor control and satisfactory renal function preservation in a carefully selected cohort of localized high-risk UTUC. Its definite application strategy and value should be further evaluated in future clinical practice.
Frequent overexpression of NECTIN-4 in CNS metastases from urothelial carcinoma.
Authors: Weiten Richard , Rieger Constantin , von Brandenstein Melanie , Storz Enno , Tolkach Yuri , Stehle Thomas , Schmidt Teresa , Glas Martin , Blau Tobias , Keyvani Kathy , Grünwald Viktor , Hölzel Michael , Heidenreich Axel , Eckstein Markus , Klümper Niklas
Published: February 2025

804

Background:
The combination of enfortumab vedotin plus pembrolizumab (EV/P) has become the new standard of care for advanced or metastatic urothelial carcinoma (mUC) due to its high efficacy. However, patients with active central nervous system (CNS) metastases were excluded from the EV-302 trial. More recently, NECTIN-4 amplifications have been identified as genomic predictors of EV response and long-term survival in patients with mUC. Additionally, early evidence suggests that EV may cross the blood-brain barrier and be effective in patients with CNS metastases. Therefore, we aimed to evaluate NECTIN-4 expression and amplification in patients with mUC involving CNS metastases.
Methods:
Immunohistochemical staining for NECTIN-4, with H-score evaluation, was performed in both non-CNS mUC (n=152) and CNS mUC patient cohorts (n=17). In addition, we developed a NECTIN-4-specific fluorescence in situ hybridization (FISH) assay to correlate NECTIN-4 copy number variations (CNVs) with membranous NECTIN-4 protein expression in CNS mUC.
Results:
Membranous NECTIN-4 protein expression was more abundant in CNS mUC (n=12/17; with H-score ≥ 100; median H-score 160; interquartile range [IQR] 250-85) than in non-CNS mUC samples (n=58/152; median H-score 40; IQR 0-140, p<0.001). Amplification data are currently being generated and will be presented at the conference.
Conclusions:
The substantial expression of NECTIN-4 in CNS metastases from UC, along with the results of the EV-302 trial and the identification of NECTIN-4 amplifications as genomic predictors of EV response and long-term survival in patients with mUC, supports the potential use of EV/P in treating patients with CNS mUC.
A phase I first-in-human clinical trial with PLZ4-coated paclitaxel-loaded micelles (PPM) in therapy-resistant non-muscle-invasive bladder cancer (NMIBC).
Authors: Pan Chong-xian , Garisto Juan , Lerner Lori , Mossanen Matthew , Dall'era Marc , Farrukh Hizra , Hynes Colleen , Parikh Mamta , Lara Primo N , Bhardwaj Urvashi , Ma Ai-Hong , Lee Joyce S. , Li Yuanpei , Lin Tzu-yin , Jiao Yanxiao , Zhao Junwei , Liu Ruiwu , Lam Kit S
Published: February 2025

806

Background:
Approximately 75% of patients with non-muscle invasive bladder cancer (NMIBC) treated with transurethral resection (TUR) followed by intravesical Bacillus Calmette-Guérin (BCG) experience cancer recurrence. When BCG-unresponsive, most patients continue to have recurrences even with newly approved therapies and nearly 30% progress to invasive stages. We developed a first-in-class bladder cancer-specific nanotherapeutic, PPM, which is administered intravesically. Our preclinical data has demonstrated PPM can selectively target bladder cancer cells and deliver paclitaxel payload into these cancer cells following intravesical or intravenous administration.
Methods:
This is a 3+3 first-in-human dose escalation trial. Eligible patients must have pathologically confirmed NMIBC, be unresponsive to intravesical BCG therapy (with or without cytotoxic chemotherapy), possess adequate vital organ function, and consent to cystoscopy with TUR for response evaluation. PPM is administered via intravesical instillation once weekly for six weeks. The trial features three dose levels, with paclitaxel doses of 25 mg, 50 mg, and 75 mg. The primary endpoints include safety and the recommended Phase II dose; secondary endpoints encompass response rate, duration of response, systemic drug absorption, and molecular correlative studies. Patients will be followed at 3 month intervals for 2 years or until disease progression.
Results:
To date, three patients with pathologically confirmed NMIBC have completed a total of 18 treatments at the first dose level without any PPM-related adverse events: one patient was unresponsive to BCG and intravesical mitomycin therapy, while the other two had BCG-unresponsive disease. Two out of the three patients achieved ongoing complete remission for over six and nine months, respectively. The third patient demonstrated persistent disease, but no progression was noted. Enrollment for Dose Level 2 is currently open.
Conclusions:
PPM has demonstrated promising clinical activity without toxicity at the first dose level in patients with BCG-unresponsive NMIBC. Data at other dose levels will be presented at the meeting (ClinicalTrials.gov identifier: NCT05519241). Clinical trial information:
NCT05519241
.
Association between proto-oncogene N-RAS transcript level and overall survival in node-negative muscle-invasive urothelial bladder carcinoma.
Authors: Kim Donghyun , Rahim Bilal G.
Published: February 2025

820

Background:
Prognostication of urothelial bladder carcinoma relies on clinicopathologic factors including histology, TNM stage and genomic profiles. The prognostic value of tumor subtyping based on gene expression signature clustering has been proposed, but their clinical value remains uncertain. Here, we retrospectively review node-negative muscle-invasive urothelial bladder carcinoma RNA-Seq data and demonstrate that “low” mRNA expression of proto-oncogene N-RAS is associated with significantly superior overall survival (OS).
Methods:
The Cancer Genome Atlas (TCGA) Pan-Cancer project batch-corrected primary tumor RNA-Seq expression profiles of 114 urothelial bladder carcinoma cases (pT2-4a pN0 M0, n=97; any pT pN1 M0, n=17) and their associated clinical data were retrieved from the cBioPortal. Cohort median was used as a reference to determine “high” vs. “low” transcript levels of N-RAS gene. Log-rank Kaplan-Meier was performed for survival analysis. Two-tailed Mann-Whitney test was performed for group comparison.
Results:
In node-negative disease group, “low” N-RAS expression (n=58) was associated with significantly superior 5-year OS compared to patients with “high” N-RAS expression (n=39) with hazard ratio (HR) for death at 0.41 (95% CI 0.19-0.86, p=0.007). N-RAS expression-associated differential OS was independent from age group (≥67 vs. <67), gender, T stage (T2 vs. T3-4a), cisplatin-based chemotherapy exposure or underlying TP53, RB1, FGFR3, RAS mutation. However, in patients with “low” N-RAS expression the 5-year OS of those who received cisplatin-based chemotherapy (n=5) was significantly superior compared to those who did not (n=53) with HR for death at 0.26 (95% CI 0.07-0.98, p=0.047). “High” N-RAS expression group was associated with higher CD274 (PD-L1) mRNA expression (x3.9 higher median value, p<0.0001) and larger portion of patients with ≥10 mut/Mb tumor mutational burden (40% vs. 23%) compared to “low” N-RAS expression group. In node-positive disease group, N-RAS expression-dependent differential OS was not present.
Conclusions:
In node-negative muscle-invasive urothelial bladder carcinoma, “low” N-RAS expression was associated with superior OS which was most pronounced in patients who received cisplatin-based chemotherapy. “High” N-RAS expression was associated with higher PD-L1 mRNA expression and tumor mutational burden. We speculate that N-RAS transcript level might be a novel biomarker for prognostication and treatment response as an adjunct to TNM stage. Further investigation is warranted.
Comprehensive investigation of CPSF3's role in the progression of bladder cancer.
Authors: Ma Zhiyang , Xu Danfeng , Wang Chenghe
Published: February 2025

829

Background:
Bladder cancer (BC) is a global health issue, with a significant number of new cases diagnosed annually. Despite advances in treatment, many patients experience recurrence or progression, emphasizing the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the prognostic significance and biological function of Cleavage and Polyadenylation Specificity Factor 3 (CPSF3) in BC.
Methods:
We analyzed CPSF3 expression using The Cancer Genome Atlas (TCGA) data and immunohistochemistry (IHC) on a cohort of 203 BC patients. A nomogram incorporating CPSF3 expression was constructed to predict overall survival (OS) and disease-free survival (DFS). In vitro experiments were conducted to assess the effect of CPSF3 knockdown on BC cell proliferation, colony formation and cell cycle distribution. Bioinformatics analyses, including Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis, were performed to explore potential mechanisms.
Results:
High CPSF3 expression was significantly associated with poor OS and DFS in TCGA and our cohort. The nomogram incorporating CPSF3 showed superior predictive performance compared to traditional models. Downregulation of CPSF3 inhibited BC cell proliferation, colony formation and transition from G1 phase to S phase. GSEA revealed enrichment of oncogentic pathways in CPSF3 high-expression phenotype. CPSF3 expression was correlated with immune cell infiltration and expression of immune checkpoints in the tumor microenvironment.
Conclusions:
Our study demonstrates that CPSF3 is a promising prognostic biomarker for BC and may play a crucial role in BC progression. The nomogram incorporating CPSF3 expression provides an improved tool for predicting BC patient outcomes. These findings suggest that CPSF3 could be a potential therapeutic target for BC treatment.
A non-coding RNA based classifier for favorable outcomes in clinically organ confined bladder cancer.
Authors: Lotan Yair , de Jong Joep , Proudfoot James A. , Daneshmand Siamak , Svatek Robert S. , Narayan Vikram M. , Gibb Ewan , Davicioni Elai , Joshi Shreyas , Li Roger , Inman Brant A. , Shah Paras H , Wright Jonathan L.
Published: February 2025

831

Background:
Long non-coding RNA (lncRNA)-based genomic profiling has suggested utility to identify a distinct tumor subgroup corresponding to a favorable prognosis in patients with bladder cancer. Here, we further evaluate a genomic classifier in a cohort of patients undergoing radical cystectomy (RC).
Methods:
Transcriptome-wide expression profiling using Decipher Bladder was performed on TURBT samples from a cohort of patients with high grade, clinically organ confined (cTa-T2N0M0) UC who subsequently underwent RC without any neoadjuvant therapy (n=226). LncRNA-based luminal favorable status was determined using a previously developed genomic classifier. The primary endpoint was overall survival (OS) following surgery. Secondary endpoints included cancer-specific mortality and upstaging at RC.
Results:
In the study, 134 patients were clinical NMIBC (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favorable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On MVA, patients with the luminal favorable subtype (vs. without) were significantly associated with lower odds of upstaging to pT3+ disease (OR [95% CI] 0.32 [0.12-0.82], p = 0.02), any upstaging (OR [95% CI] 0.41 [0.20-0.83], p = 0.01), and any upstaging and/or pN+ (OR [95% CI] 0.50 [0.25-1.00], p = 0.05). Luminal favorable bladder cancer was significantly associated with better OS (HR 0.33 [95% CI 0.15-0.74], p=0.007).
Conclusions:
This study validates the performance of the genomic classifier for identifying urothelial carcinomas with a luminal favorable subtype, harboring less aggressive tumor biology.
Extracellular DNA in patients with urothelial carcinoma of the bladder.
Authors: Palacka Patrik , Kováčová Hana , Mikolášková Iveta , Suchánková Magda , Paulovičová Mária , Kollárik Boris , Celec Peter , Hunákova Ľuba
Published: February 2025

834

Background:
Higher concentration of extracellular DNA (ecDNA) in plasma of subjects with various cancers is associated with worse prognosis. The association of ecDNA and its subcellular origin – nuclear DNA (ncDNA) and mitochondrial DNA (mtDNA) with urothelial carcinoma of the bladder (BC) is unexplored. Deoxyribonuclease (DNase) can cleave ecDNA and modulate the observed association. The objective of this study was to identify the potential differences in ecDNA, ncDNA, mtDNA and DNase between patients with non-muscle-infiltrating BC (NMIBC) and muscle-infiltrating BC (MIBC) compared to controls.
Methods:
We analyzed a population of 62 individuals with BC (44 males, median age 67.5 years), 20 had Ta stage, 26 T1 stage (NMIBC) and 16 T2–T3 stage (MIBC). The control group consisted of 15 males and 6 females without history of cancer, median age 67.3 years. EcDNA was quantified fluorometrically after isolation from double centrifuged plasma. The subcellular origin of ecDNA was analyzed using quantitative real time PCR targeting specific nuclear and mitochondrial sequences. DNase activity was assessed using the single radial enzyme diffusion method. For statistical analysis, basic nonparametric tests were used.
Results:
In patients with BC compared to controls, we identified significantly higher ecDNA (median 15.0
v
11.7 ng/ml, P=.021) and ncDNA (median 4707
v
2136 GE/ml, P=.0046), but not mtDNA and DNase. Moreover, we determined a higher activity of DNase (median 2.3 vs 1.9 ng/ml, P=.0084) in subjects with NMIBC (Ta+T1)
v
MIBC. By mutual comparisons of all subgroups, following significant differences were recognized: ecDNA and ncDNA in MIBC
v
controls (P=.0065 and P=.0127, respectively) and DNase for Ta
v
MIBC (P=.0177). In addition, we detected a significant correlation on a stage of BC and rising ecDNA concentrations (P=.0076).
Conclusions:
In this study, we showed higher plasma ecDNA and ncDNA in patients with MIBC than controls and lower DNase activity in MIBC compared to NMIBC. The ecDNA concentrations increased with rising tumor stage. These results suggest a possible diagnostic and a likely prognostic value of ecDNA and DNase in BC. Further studies will focus on a potential association between plasma ecDNA and urinary ecDNA, which are assessed non-invasively and more frequently. This study was supported by the Ministry of Education, Science, Research and Sport of the Slovak Republic (grant number : VEGA 1/0090/22), the Slovak Research and Development Agency (grant number: APVV-22-0231) and OncoReSearch. Key Words: Bladder Cancer. Extracellular DNA. Nuclear DNA. Mitochondrial DNA. Nuclease.
Changes in circulating tumor cells (CTCs) and HER2 expression in evaluating the efficacy of neoadjuvant disitamab vedotin plus toripalimab treatment in patients with muscle-invasive bladder cancer (MIBC).
Authors: Cao Yudong , Li Ruojing , Wang Shuo , Ma Jinchao , Ji Yongpeng , Lin Chen , Du Peng
Published: February 2025

837

Background:
Disitamab vedotin (DV) combined with toripalimab has shown promising efficacy as neoadjuvant therapy for MIBC, with a pathological CR (pCR) rate of 62.1% in the previous report (2024 ASCO). In real-world practice, many patients who achieved clinical complete response (cCR) after neoadjuvant therapy, confirmed by re-TURBT, imaging, and urine cytology, opted for bladder-preserving treatment (BPT). However, biomarkers to confirm the absence of residual tumors in cCR pts are lacking. This study aims to evaluate the correlation between changes in CTCs and HER2+ CTCs during neoadjuvant therapy with clinical efficacy outcomes in MIBC.
Methods:
18 pts were retrospectively included from July 2023 to July 2024. The primary endpoint was to assess the correlation between changes in CTCs and HER2+ CTCs before and after neoadjuvant therapy, and clinical efficacy (cCR or non-cCR). Eligible pts had previously untreated MIBC (cT2-T3N0-1M0) with HER2 expression of IHC ≥ 2+. Pts received DV (2 mg/kg) plus toripalimab (3 mg/kg) every two weeks for six cycles, followed by radical surgery or BPT for cCR pts (choice made after communication between the physician and the pts). cCR criteria included no residual tumor confirmed by re-TURBT, no evidence of tumor on imaging, and negative urine cytology. Peripheral blood samples were collected to measure CTC counts and HER2 phenotype by HER2-iFISH.
Results:
Among 18 pts, 15 (83.3%) achieved cCR, while 3 pts (16.7%) were in the non-cCR group, including 2 pts with cPR confirmed as pT2N0 postoperatively, and 1 pt with clinical progression (cPD). All 15 cCR pts underwent BPT. There were no significant differences in the total CTCs and HER2+ CTCs between the cCR and non-cCR groups before treatment (P = 0.426, P = 0.654, respectively). After neoadjuvant therapy, CTC and HER2+ CTC counts were significant lower in the cCR group compared to the non-cCR group (P = 0.039, P = 0.005, respectively). Only 1 (6.7%) cCR pt had detectable HER2+ CTCs post-treatment, while all 3 non-cCR pts had measurable HER2+ CTCs.
Conclusions:
Changes in CTCs and HER2+ CTCs correlated with clinical efficacy outcomes of DV plus toripalimab neoadjuvant therapy, particularly in HER2+ CTCs. CTCs and CTC HER2 expression may serve as potential biomarkers for evaluating clinical efficacy and guiding treatment strategies in MIBC.

The clinicopathological characteristics of the 18 MIBC patients.

Characteristic
All patients (n=18)
cCR (n=15)
non-cCR (n=3)

P
value

Clinical T stage, n (%)

1.00

cT2
10 (55.6)
8 (53.3)
2 (67)

cT3
8 (44.4)
7 (46.7)
1 (33)

Clinical N stage, n (%)

1.00

cN0
15 (83.3)
12 (80.0)
3 (100)

cN1
3 (16.7)
3 (20.0)
0 (0)

HER-2 expression, n (%)

0.44

2+
15 (83.3)
13 (86.7)
2 (66.7)

3+
3 (16.7)
2 (13.3)
1 (33.3)
Discordance in HER2 expression in primary and recurrent/metastatic lesions of upper tract urothelial carcinoma: A study focusing on temporal heterogeneity.
Authors: Ye Jianjun , Liao Xinyang , Wang Qihao , Zheng Lei , Chen Kai , Wei Qiang , Bao Yige
Published: February 2025

839

Background:
The promising performance of HER2 antibody–drug conjugates (ADC) in clinical trials suggested that HER2-targerted therapy, particularly ADCs, may be a suitable treatment option for metastatic UTUC. However, we have observed cases where ADCs were ineffectiveness for recurrent/metastatic lesions in patients with HER2-positive primary UTUC. Thus, we conducted a retrospective study of UTUC patients to investigate the specific HER2 expression in paired primary and recurrent/metastatic lesions.
Methods:
Data of 290 UTUC patients who underwent radical nephroureterectomy at West China Hospital of Sichuan University from Jan 2020 and Oct 2023 without neoadjuvant treatment were retrospectively included. The HER2 expression was independently evaluated through immunohistochemistry by our professional genitourinary pathologists. HER2 2+ and HER2 3+ were considered HER2-positive whereas others were considered HER2-negative.
Results:
A total of 249 patients had HER2 expression evaluation of their specimens, with 92 patients (39.36%) showing HER2-positivity (IHC HER2 2+ or 3+). During rigorous follow-up, 31 patients (12.45%) developed local recurrence or distant metastasis. The majority of those patients had locally advanced UTUC (pT ≥ 3) and high grade disease. We observed discordance in HER2 expression between primary and recurrent/metastatic lesions in 22 cases (70.97%), with 9 cases (29.03%) showing an increase in HER2 expression and 13 cases (41.94%) showing a loss of HER2 expression. The conversion from HER2 negative to positive or vice versa occured in 5 cases (16.13%) and 10 cases (32.26%), respectively. Notably, all primary lesions with HER2 0 expression obtained HER2 expression in recurrent/metastatic lesions (5/5, 100%).
Conclusions:
Our findings highlight the discordance in HER2 expression between primary and recurrent/metastatic lesions in UTUC, underscoring the need for further investigation and potential modifications in disease management.
Pathological subclassification of T3 upper tract urothelial carcinoma: Complementary evidence for existing guidelines.
Authors: Zheng Lei , Ye Jianjun , Wang Qihao , Wei Qiang , Bao Yige
Published: February 2025

841

Background:
According to the current guidelines, upper tract urothelial carcinoma (UTUC), which encroaches beyond the muscularis propria but does not invade peripheral organs or perirenal fat, is classified as pathological T3 (pT3). However, the current classification definition of pT3 fails to meet clinical needs due to the significant heterogeneity of pT3 UTUC in terms of biological features and oncological outcomes. Therefore, the aim of this study was to explore the effect of subclassifying pT3 UTUC on oncological outcomes based on a large UTUC cohort from Southwest China.
Methods:
Data of pathologically confirmed UTUC patients treated with radical nephroureterectomy (RNU) treatment at West China Hospital of Sichuan University from May 2003 to June 2019 were retrospectively collected. Only patients with a diagnosis of initial pT3 and complete follow-up information were included in the study. pT3 was subclassified into pT3a (defined as tumor invasion of the ureteral adventitia or renal parenchyma) and pT3b (defined as tumor invasion of the ureter or peri-pelvic fat). The primary endpoints included cancer-specific survival (CSS), overall survival (OS) and recurrence-free survival (RFS).
Results:
A total of 326 patients with initial pT3 UTUC were finally included. According to our proposed subclassification, 232 cases were in pT3a group and 94 cases were in pT3b group. K-M analysis showed that the patients in pT3b group had significantly worse OS, CSS and RFS than those in pT3a group. Multifactorial Cox regression analysis demonstrated that patients in pT3b group had a 1.86-fold (95% CI, 1.19-2.91) risk of death, a 1.95-fold (95% CI, 1.21-3.17) risk of disease-related death and a 1.78-fold (95% CI, 1.21-3.17) risk of disease recurrence than those in the pT3a group. After adjustment for tumor size, tumor grade and lymph node metastasis the above findings remained statistically significant.
Conclusions:
Based on the presence or absence of invasion of the ureter and peri-pelvic fat, our study proposes a novel pT3 subclassification, which provide physicians with invaluable insight into better stratification of pT3 UTUC patients and provide a basis for individualized treatment.
PPARG protein expression in advanced urothelial carcinoma and selection for response to FX-909, a first-in-class PPARG-targeting agent.
Authors: Gjini Evisa , Motley William , Joshi Adarsh , Kakrecha Bijal , Mertz Jennifer , Williamson Kaylyn , Kirov Stefan , Bowden Michaela
Published: February 2025

856

Background:
FX-909, a PPARG inverse agonist, is being evaluated in a first-in-human, dose escalation and expansion study in patients with advanced urothelial carcinoma (UC; NCT05929235). PPARG drives development of UC and its expression is associated with the luminal lineage, which accounts for ~65% of all advanced UC patients
2
. An IHC prototype assay was developed to detect PPARG expression in formalin-fixed paraffin-embedded UC tissues. Our data show that PPARG protein expression correlated with PPARG RNA expression in a retrospective cohort of archival tissue from high-grade localized UC.
Methods:
Commercial antibodies, clones C26H12, K.242.9 and E-8, were tested and validated using UC and control normal tissues. The E-8 clone was selected for further development based on demonstration of good specificity, sensitivity, range, and linearity. Specificity of the PPARG staining was demonstrated in cell lysates, where PPARG expression level was confirmed by Western blot (HEK293, BC3C, UMUC9, and RT112). Assay performance was evaluated in a cohort of 25 high-grade localized, stage III-IV UC patient samples. Semi-quantitative analysis [percent (%) tumor score and H-score] was conducted by a pathologist. Gene expression values from RNAseq were normalized by transcripts-per-million (TPM). Molecular classification was performed using non-negative matrix factorization rank 5 following the Robertson method
3
derived from RNAseq.
Results:
The E-8 clone detected a broad range of PPARG expression, with a predominantly nuclear staining pattern at staining intensities from 0 to +3. Each sample exhibited different staining intensities, highlighting the heterogeneity of PPARG expression. Eighty-eight percent of cases showed PPARG expression in more than 50% of their tumor cells (22 out of 25). H-scores varied from 0 to 270 (Median H-Score = 146), where 64% of the cases showed a moderate PPARG expression with H-scores ranging between 100 and 200. PPARG protein expression quantitated based upon the % tumor area with 2+ or greater staining correlated with RNA expression levels (Spearman correlation coefficient r = 0.66; p-value <0.01). Similarly to previous data
2,5
, 52% of the cases in this cohort were of luminal lineage. The median RNA expression level of PPARG was significantly higher in the luminal subgroup compared to the non-luminal subgroup (6.0 Log2[TPM+1] vs 3.53 Log2[TPM+1], p <0.01).
Conclusions:
These data show the IHC assay is sensitive and specific for the detection of PPARG expression in advanced UC with utility to identify patients with potential to respond to FX-909, a first-in-class PPARG-targeting agent
4
. 1. Sims R, AACR 2023, Fl; 2. Motley W, et al. EORTC 2022; 3. Robertson AG, et al. Cell 2017; 4. Iyer G, et al. ASCO GU 2024, CA; 5. Kirov S, AACR-NCI-EORTC 2023, MA.