bluuebunny/crossref_metadata_2025_split huggingface dataset:
A meta-analysis assessing objective response rates with first-line systemic treatment options in locally advanced/metastatic urothelial carcinoma.
Authors: Saxena Akshat , Naqvi Syed Arsalan Ahmed , Tripathi Nikita , Khan Muhammad Ali , Bibi Arifa , Ballouz Tara , Abdul-Muhsin Haidar , Tyson Mark , Riaz Irbaz Bin , Bryce Alan Haruo , Singh Parminder 
Published: January 2024

639 Background: Immunotherapy combined with chemotherapy (IO/C) as the first-line management of locally advanced or metastatic urothelial carcinoma (LA/mUC) has been investigated in multiple trials with conflicting outcomes. Therefore, we conducted a meta-analysis of available trials to compare objective response rates (ORR) of this combination regimen, both in overall and in cisplatin-ineligible populations. Methods: EMABSE and MEDLINE were searched from 2000 through July 20th, 2023, to identify phase II and III clinical trials assessing IO, C or both in LA/mUC. Main outcome of interest was objective response rates (ORR) as defined in the included trials. An inverse variance random-effects meta-analysis was performed to estimate pooled ORR using the restricted maximum likelihood estimation method. Subgroup differences were assessed among IO/C, IO alone, and C alone. The threshold for statistical significance was established at 0.1. Results: Of 5975 citations identified, a total of 26 trials with a total of 4,628 participants were included in this systematic review. In the overall group, the ORR in IO/C trials (5 trials, 1,236 patients) was 44.70% (95% CI: 21.88%- 70.0%). In IO trials (7 trials, 2,189 patients), ORR was 23.68% (19.55%- 28.36%) and in C trials (26 trials, 4,628 patients) was 43.46% (37.43%-49.68%]). In the cisplatin-ineligible group, the ORR in IO/C trials (2 trials, 240 patients) was 60.06% (33.38%-81.86%), in IO trials (6 trials, 1,103 patients) was 26.15% (23.01%; 29.56%), and in C trials (8 trials, 767 patients) was 42.45% (35.67%-49.52%). In terms of subgroup differences, the difference in ORR was statistically significant between IO/C and IO trials (p= 0.0844) and between IO and chemotherapy trials (p< 0.0001) in the overall population. Similarly, we found a statistically significant difference in ORR between IO/C and IO (p= 0.0108) and between IO and chemotherapy trials (p< 0.0001) in the cisplatin-ineligible population. No statistically significant differences were observed between IO/C and C alone. Conclusions: First-line IO/C may achieve a better objective response compared to IO alone in patients diagnosed with locally advanced/metastatic UC. Although, there appears to be a trend of greater benefit with IO/C compared to C alone, the difference was not statistically significant. The results will be updated as soon data from new trials (CheckMate 901 and EV 302) becomes available which could offer new insights. [Table: see text]
Effect of type of antibiotics (Abx) on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Hobeika Charbel , Dawsey Scott , Patgunarajah Ubenthira , Lynn David , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa 
Published: January 2024

640 Background: Use of Abx was associated with worse overall survival (OS) and progression-free survival (PFS) in our real-world cohort of mUC pts treated with ICI. (ASCO 2023). We now report the effect of type of Abx on ICI outcomes. Methods: In our cohort of 335 pts with mUC treated with ≥2 cycles of ICI with atezolizumab (A) or pembrolizumab (P) at CCF between 2015 and 2023, Abx class used in at least 20 pts was included. PFS and OS were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression method. Results: Of 335 pts, 26.27% received A and 73.73% received P. Median follow-up was 26.8 mos. Details of type of Abx (cephalosporins (CPH), fluoroquinolones (FQ), penicillins (PCN) and trimethoprim-sulfamethoxazole (TMP-SMX), timing (30 or 60 (d) pre or post ICI start) and OS/PFS are shown in the Table. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with worse OS (10.97 vs 16.03 mos.; (HR) 1.6 [1.2 -2.1], p=0.0004). Abx use within 30 (d) post ICI was associated with worse OS (6.9 vs 14.39 mos, p=0.008). Individual Abx and effect on OS and PFS are shown in Table. On MVA Cox regression analysis, Abx use within 60 (d) post ICI start was associated with worse PFS (3.12 vs 5.67 mos., HR 1.4; p=0.015). Conclusions: In our large cohort of pts with mUC treated with ICI, Abx PCN, CPH and FQ, within 30 and 60 (d) prior to starting ICIs demonstrated worse OS, Abx used after 30 and 60 (d) of ICI demonstrated worse OS and PFS, especially with CPH and PCN but not FQ. These findings have the potential to influence clinical practice, including using a higher threshold for prescribing antibiotics to pts with mUC when planned for or on ICI and the choice of Abx used. [Table: see text]
Real world experience of FGFR gene alterations and clinical outcomes in advanced/metastatic urothelial cancer in Japan: MONSTAR-SCREEN database study.
Authors: Matsubara Nobuaki , Osawa Takahiro , Abe Takashige , Oya Mototsugu , Nishimoto Koshiro , Iwahori Toshiyuki , Tsuchiya Hiroaki , Murota Maiko , Yoshida Masaki , Tatematsu Yohei , Nakano Yosuke , Eto Masatoshi , Nonomura Norio 
Published: January 2024

647 Background: Gene alterations (GA) in fibroblast growth factor receptors ( FGFR) may be oncogenic drivers in urothelial cancer (UC). However, the association between FGFR GA status and the prognosis with platinum-based chemotherapy has not been well investigated, especially in Asian patients. This study aims to elucidate the proportion and prognosis of FGFR2 or 3 (2/3) GA-positive advanced or metastatic UC (a/m UC). Methods: This study included patients registered during 2019 and 2022 in the “MONSTAR-SCREEN” database, where FoundationOneLiquid (F1L) was used for detecting 324 cancer-related genes, including FGFR. Analyzed FGFR2/3 GA variants included FGFR3 mutations (R248C, S249C, G370C, and Y373C) and FGFR2/3 fusions (FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, and FGFR3-BAIAP2L1). The positive ratio of FGFR2/3 GA and other gene alterations except FGFR was obtained at registration in eligible patients; besides, FGFR2/3 GA status was also evaluated after systemic treatment. Progression-free survival (PFS) in each treatment line was estimated, summarized by FGFR2/3 GA positive/negative. Results: Among the registered 2,224 cancer patients in this database, 138 eligible a/m UC patients were included (median age [SD] 72.0 [9.1] years for all; 95 males [68.8%]). The primary tumor site was the bladder in 70 patients (50.7%), renal pelvis in 50 patients (36.2%), and ureter in 18 patients (13.0%). FGFR2/3 GA was positive in 16 patients (11.6% [95% confidence interval: 6.8, 18.1]); the proportion of other typical gene alterations was 92.8%, 41.3%, 23.2%, and 23.2% in TP53, TERT, ARID1A and BRCA2, respectively. F1L was performed both before and after systemic treatment twice or more in 55 patients (39.9%). The FGFR concordance was analyzed in 55 patients available for both before and after treatment F1L results. Among them, 3 of the 6 FGFR2/3 GA-positive patients (50.0%) remained positive, and 1 of the 49 FGFR2/3 GA-negative patients (2.0%) before systemic treatment turned positive after treatment. The median PFS after first-line treatment was 6.8 months in FGFR GA-positive and 6.4 months in the negative patients. The estimated survival rate after first-line treatment was also similar between FGFR GA-positive and -negative patients at 12 months (68.8% vs. 81.0%). Conclusions: The results showed a similar trend to previous studies, where FGFR GA was reported in approximately 20% of metastatic UC patients. No difference was found in the PFS and the estimated survival rate by FGFR2/3 GA-positive or -negative patients. Our data showed that treatment pressure did not alter the FGFR status commonly.
Performance of a tumor-informed molecular residual disease (MRD) assay in resected bladder cancer with mixed or pure variant histology: Analysis of a real-world multicenter cohort.
Authors: Kommalapati Ajitha , Laliotis George , Rich Jordan , Cumarasamy Shivaram , Rivero Samuel , Sharma Shruti , Palsuledesai Charuta C , Malhotra Meenakshi , Galsky Matt D. , ElNaggar Adam , Liu Minetta C. , Sfakianos John P. , Peyton Charles , Ferguson James , Basu Arnab 
Published: January 2024

649 Background: Circulating tumor DNA (ctDNA)-based MRD assays can detect clinically occult disease with high sensitivity and specificity in patients with solid tumors. Previous trials that evaluated MRD testing in bladder cancer, such as ABACUS and IMVigor010, enrolled patients with a predominant urothelial carcinoma component. Given the known histological and molecular heterogeneity in urothelial carcinoma, we examined the prognostic value of a tumor-informed MRD assay in bladder cancer patients with mixed or pure variant histologies (M/VH). Methods: This retrospective study analyzed the results of post-cystectomy longitudinal ctDNA testing from a multi-institutional database of patients with urothelial carcinoma (n=205). A personalized, tumor-informed assay (Signatera, Natera, Inc.) was used for the detection and quantification of ctDNA. Patients with M/VH and at least 3 months of postoperative follow-up data on relevant demographic, clinical, pathologic, and NGS variables were eligible for inclusion. Time-dependent Cox regression analyses were performed for disease-free survival (DFS) based on ctDNA during the MRD window (<12 weeks from surgery, N=29) and surveillance window (>12 weeks post-surgery or post-AT, N=29). Multivariable regression was performed to adjust hazards for clinicopathologic factors predicting DFS. Results: Of the 205 patients, 46 (74% male, median age: 69 years) met the inclusion criteria for analysis. Whole exome sequencing of tumor tissue revealed that TP53 (45.7%), ARID1A (32.6%), and KDM6A (30.4%) were the top three genes with somatic mutations. Twenty-seven (59%) patients received neoadjuvant therapy, 37% of whom (10/27) also received adjuvant therapy. ctDNA-positivity during the MRD window and during surveillance was strongly associated with poor DFS (MRD window: HR=4.93, 95%CI: 1.77-20.77, p=0.03; surveillance: HR=28.3, 95% CI: 3.52-3660, p<0.001). None of the serially ctDNA-negative patients (N=25) recurred, whereas 58.9% (10/17) of patients who were ctDNA-positive anytime post-surgery recurred at a median follow-up of 9 months from the date of surgery, range: 3.1-36.4 months). When adjusted for all other risk factors, ctDNA-positivity anytime post-surgery was the only significant predictor of recurrence (HR=55.26, 95%CI: 5.3-7648, p<0.00001). Conclusions: Personalized, tumor-informed ctDNA testing can identify patients with mixed or variant histology bladder cancer who are at high risk of recurrence. Further studies are warranted to evaluate the potential benefit of ctDNA-guided adjuvant therapy in this patient population.
Genomic comparison of urothelial mucinous adenocarcinoma and colorectal mucinous adenocarcinoma biomarkers and therapeutic implications.
Authors: Paster Irasema Concepcion , Barker Kenneth , Fernandez Ana Jose , Guillen-Rodriguez Jose , Chipollini Juan , Recio-Boiles Alejandro 
Published: January 2024

650 Background: Urothelial mucinous adenocarcinoma (UC-MUC-AC), arising from the urothelium, is a rare condition (<2%), typically presenting at an advanced stage with an unfavorable prognosis. The lack of a standard treatment protocol adds complexity, requiring the extension of treatments from UC or organ-specific MUC-AC such as colorectal. Notably, UC-AC bears a histopathological resemblance to intestinal tumors, constituting the predominant subtype. Alternatively, treatment decisions based on gene expression similarities in lieu of histological similarities are an evolving concept in rare cancers. This is an unexplored area in UC-MUC-AC treatment, prompting our hypothesis that an all-encompassing genomic profile could reveal analogous biomarkers shared with CRC-MUC-AC. Methods: Three techniques: DNA sequencing, RNA sequencing (WTS), and immunohistochemistry (IHC) sequencing (protein) with varying measures for gene expression were analyzed at Caris Life Sciences in Phoenix, AZ. Histopathology was used to categorize five cancer site groups: (1) UC arising in the bladder, ureter, urethra, or renal pelvis with any transitional cell carcinoma (TCC)-non-MUC-nonAC [N156 samples], (2) UC nonTCC-nonMUC-AC [N83], (3) UC-MUC-AC [N16], (4) CRC-MUC-AC [N3100] and (5) CRC nonMUC-AC [N38205]. Our primary aim was to determine which group was closest to Group 3, our control. Our secondary aim was to determine if Group 2 was genetically closer to Group 1 or 5. Only genes with positive expression were included in the cluster analysis. ANOVA analysis was conducted to further explore the relationships between the groups. A log transformation was performed to achieve normality. To further investigate pairwise comparisons, a post hoc Dunnett test was employed. Results: In our first analysis, Group 3 UC-MUC-AC gene expression ratio was predominately associated with UC Groups 1 & 2 (24 of 33), and farther to CRC Groups 4 & 5 (9/33) (all p-values >0.05). In the second analysis, the ANOVA overall model comparing gene expression between the histological groups 1, 2 & 5 was statistically significant (p=0.0018). The Dunnett test revealed a farther difference between Group 2, UC nonTCC-nonMUC adenocarcinoma, and 5, CRC non-MUC-AC (p-value =0.001), but closest between Group 2 and 1, UC-TCC-nonMUC-nonAC (p =0.100). Conclusions: Our findings indicate that next-generation sequencing technology has the potential to aid in treatment decisions based on the site of origin, such as UC-AC, rather than relying on traditional histopathological descriptive approaches for extrapolating evidence from treatment protocols used for other cancer origins like CRC. Future research on artificial intelligence could aid physicians with more informed treatment decisions by providing additional insight into how closely tumors match cancer types' genomic and transcriptomic signatures.
Predictive roles of NETs and IgG in neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Shang Bing-Qing , Gu Zhaoru , Cui Honglei , Xie Rui-Yang , Wu Jie , Shi Hongzhe , Bi Xin-Gang , Qu Wang , Zhang Wen , Zhou Aiping , Zhang Kaitai , Feng Lin , Shou Jianzhong 
Published: January 2024

659 Background: Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC), in the neoadjuvant setting. However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. Besides, NETs and IgG could reflect the immune response, even may induce immune tolerance. In MIBC, the predictive role of NETs or IgG in chemotherapy resistance is unclear. Methods: This study included 54 patients with MIBC undergoing neoadjuvant chemotherapy. Immunohistochemical staining with NETs was performed on tumor primary lesions before chemotherapy, and the staining intensity was scored. Serum IgG levels in the pre-treatment baseline and 1 month after chemotherapy were also measured for these patients. Results: Citrullinated histone H3 (H3Cit) as a hallmark of NETs, was an independent predictor of chemotherapy resistance as determined by the multivariate logistic regression analyses [OR=5.94, 95% CI 1.20–45.50, P=0.045]. Additionally, in patients with favorable chemotherapy response, serum IgG levels significantly decreased after 1 month of treatment (P=0.0018), while in those with poor response, there was no significant change. Conclusions: The baseline levels of NETs and the change of IgG after 1-month treatment demonstrated predictive capabilities during neoadjuvant chemotherapy, possibly reflecting the immune status. MIBC patients with high NETs and IgG levels were resistant to neoadjuvant chemotherapy, providing new insights into the treatment of MIBC. However, these results require further validation through larger sample studies. Further validation of our findings could provide a theoretical basis regarding NETs inhibitors or IgG antibodies combined with chemotherapy strategy.
Association of perioperative acute kidney injury with oncological outcomes in patients who undergo radical cystectomy: A multicenter retrospective study.
Authors: Fujita Naoki , Momota Masaki , Tanaka Toshikazu , Hosogoe Shogo , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara 
Published: January 2024

660 Background: Acute kidney injury (AKI) is a frequent complication in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). Previous studies have reported that AKI during cancer treatment was associated with poor oncological outcomes in several malignancies. Moreover, we previously have reported the negative impact of neoadjuvant chemotherapy-induced AKI on oncological outcomes in patients with MIBC. However, the impact of perioperative AKI on oncological outcomes in patients who undergo RC remains unclear. Methods: This multi-institutional retrospective study included 798 patients with MIBC who underwent RC. AKI was defined according to the KDIGO criteria. Stage 1 AKI was diagnosed with an increase in serum creatinine by just 0.3 mg/dL. Patients were divided into two groups: patients who developed AKI after RC (AKI group) and patients who did not (non-AKI group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the impact of perioperative AKI on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age and follow-up period were 70 years and 64 months, respectively. Of the 798 patients, 408 (51%) developed AKI after RC. Approximately 73% AKI were stage 1 AKI. RFS, CSS, and OS in the AKI group were significantly shorter than those in the non-AKI group ( P = 0.003, P = 0.035, and P < 0.001, respectively). After adjustment for confounding variables, AKI was significantly associated with shorter RFS (hazard ratio [HR] 1.357, P = 0.019), CSS (HR 1.345, P = 0.042), and OS (HR 1.344, P = 0.009). Conclusions: Perioperative AKI was associated with poor oncological outcomes in patients with MIBC who underwent RC. [Table: see text]
Comprehensive analysis of targetable alterations in urachal cancer by NGS.
Authors: Benjamin David Joseph , Adeyelu Tolulope Tosin , Elliott Andrew , Darabi Sourat , Lee Thomas , McKay Rana R. , Oberley Matthew James , Rezazadeh Arash 
Published: January 2024

663 Background: Urachal cancer (UrC) is a rare genitourinary cancer with molecular drivers commonly found in colorectal cancer and harbors fewer actionable alterations. Although prior studies have identified genomic alterations associated with UrC, these lack comprehensive genomic profiling, often using targeted panels, and lack RNA interrogation. This study presents detailed characterization of molecular profiles and the tumor microenvironment of real-world UrC patient samples. Methods: UrC samples (n = 42) were profiled using next-generation sequencing (NGS) of DNA and RNA. Prevalence was calculated for pathogenic SNVs/Indels and copy number amplifications, dMMR/MSI status assessed by IHC and NGS, PD-L1 expression measured by IHC, and TMB-H defined as ≥ 10 mut/Mb. Immune cell fractions of TME were estimated using RNA deconvolution. Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Histological features were reviewed by a genitourinary pathologist. Results: UrC samples were collected from 19 males and 23 females with a median age at sample collection was 58.5 years (range: 24-86 years). Pathology review revealed the majority were adenocarcinomas (n=41/42, 97.6%), including mucinous (n=17/41, 41.5%) and enteric adenocarcinomas (n=10/41, 24.4%). Pathogenic variants were most commonly observed in TP53 (n = 35, 83.3%), KRAS (n=15, 36%), GNAS (n=5, 12%), SMAD4 (n=4, 10%), PIK3CA (n=4, 10%), STK11 (n=3, 7%), BRCA2 (n=3, 7%), ARID1A (n=2, 5%), PTEN (n=2, 5%), ERBB2 (n=2, 5%), BRAF (n=2, 5%), and APC (n=2, 5%). MAPK pathway alterations were present in 52.3% (n=22) overall, with increased MAPK pathway activation in MAPK-altered UrC (median MPAS: 0.77 vs -0.61, p = 0.066). Loss of heterozygosity was prevalent (n = 9, 29%). While no UrC tumors had dMMR/MSI, 5% (n=2) were TMB-H and 9% (n=3) were PD-L1+. The mean fraction of T cells – CD8 (0.4%) and monocytes (0.0%) represented a smaller fraction UrC TME composition compared to macrophages M1 (5.19%) and neutrophil (6.4%). The median NK cell fraction was significantly higher in MAPK-altered UrC patients (3.5 vs 2.7%, p = 0.022), yet a transcriptional signature of response to immunotherapy (IFN-g) was similar between MAPK-altered and MAPK-WT UrC patients (median IFN: -0.366 vs -0.384, p = 0.052). Conclusions: This study provides a comprehensive molecular characterization of UrC and the associated immune landscape. While MAPK and DNA repair gene alterations were common, UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials.
Pulsed electromagnetic field therapy's effect on bladder cancer cell line HT-1376.
Authors: Sandberg Maxwell , Whitman Wyatt , Ross Christina , Tsivian Matvey , Walker Stephen 
Published: January 2024

666 Background: Pulsed electromagnetic field therapy (PEMF) is a magnetic waveform energy that can be targeted for delivery to cells and/or patients. It is noninvasive, and to date no reported negative side effects exist. Recently, its use as a therapeutic for cancer has come into focus. However, to our knowledge, no study has examined the effect of PEMF on bladder cancer at the cellular level. In this study, we sought to examine how PEMF altered a bladder cancer cell line (HT-1376) at the genomic level. Methods: HT-1376 cells were cultured, and cells were plated into either a control plate (no PEMF) or experimental plate (PEMF). The experimental cells were subjected to PEMF which had an oscillating magnetic field ranging from 1.5 MilliTesla (mT) to 16 mT at 30 Hertz, 1 hour each day for 3 total days. RNA was isolated from both control and experimental cell plates on day 3 and assayed on whole genome microarrays. Day 3 control samples from HT-1376 were compared to day 3 PEMF treated cells. Results were analyzed using Ingenuity Pathway Analysis. Results: Data from genomic analysis revealed that many cancer-related pathways were altered after treatment with PEMF in HT-1376. Relevant cancer pathways downregulated after PEMF treatment in HT-1376 cells compared to controls were the PIK3/AKT pathway (p=8.1e-61), neuroinflammation signaling pathway (p=2.3e-60), and external growth factor pathway (p=4.8e-35). Upregulated pathways after PEMF treatment relative to controls were the p53 signaling pathway (p=1.1e-06), endocannabinoid cancer inhibition pathway (p=1.1e-38), and the T-cell exhaustion signaling pathway (p=3.7e-22). The table also lists cancer relevant genes up and downregulated after PEMF treatment. Conclusions: PEMF appears to alter the tumor profile of bladder cancer cell line HT-1376. Key pathways implicated in cancer pathogenesis were altered after treatment. Further, after treating HT-1376 bladder cancer cells with PEMF for 3 days, significant alterations in gene expression occurred. This has widespread implications for prognosis, management, and treatment of bladder cancer. Ultimately, PEMF may represent an exciting new non-invasive therapeutic in bladder cancer, which necessitates further research.[Table: see text]