bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
The potential of transcriptomic profiling to predict immune-checkpoint inhibitor (ICIs) response in locally advanced (La) and metastatic urothelial carcinoma (mUC).
Authors: Caramelo Belen , Muñoz Unceta Nerea , Freire Javier , Varela Ignacio , Martin David , Del Carmen Sofía , Azueta Ainara , Diaz Pilar , Garcia-Berbel Pilar , Sagastibelza Marinelarena Naiara , Rey-Cárdenas Macarena , Castellano Daniel , Climent Miguel Ángel , Puente Javier , Irure Juan , Revuelta Laura , Genre Fernanda , Cacho Diego , Gómez Javier , Duran Ignacio
Published: January 2024

668

Background: Immune checkpoint inhibitors (ICIs) have proven to be an effective therapy for locally advanced (La) and metastatic (mUC) urothelial carcinoma. However, response rates are typically modest, and patient (pt) selection remains a challenge, especially in the era of ICIs-based combos. The current study analyzes the differential RNA expression as a predictor of ICI response or resistance in La/mUC. Methods: Clinical information and formalin-fixed paraffin embedded (FFPE) samples from pts with La/mUC treated with single agent ICIs [2014 -2021] were obtained and RNA sequencing (RNA-seq) analysis performed. According to response, pts were assigned to one of these three groups: Primary resistant [PR] (progressive disease (PD) as the best response); Secondary resistant [SR] (initial response followed by PD); and Long responders [LR] (stable disease/partial or complete response maintained > 16 months). Results: Clinical data and FFPE samples from 46 patients were available. Nineteen, twelve and fifteen pts respectively were in the PR, SR and LR groups. Clinical characteristics were well-balanced among groups, except for higher percentage of liver metastasis in PR and SR pts. The median overall survival was 11.2 and 18.2 months for the PR and the SR groups and has not yet been reached for the LR cohort, where 80% of the pts remain alive, with 50% achieving complete response. RNA-seq analysis unveiled distinct patterns of differential gene expression in the resistance groups compared to the LR. Notably, an upregulation of the epithelial-mesenchymal transition pathway was observed, with interleukin 2 emerging as a potential surrogate marker of this activity. Additionally, an overactivation of the KRAS pathway was evident, irrespective of its mutational status. Furthermore, in a comparison between the two resistance groups, the SR group displayed increased activation of DNA damage control mechanisms. Conclusions: Our RNA-seq analysis could provide relevant information and holds promise as a valuable tool for predicting responses to ICIs in La-mUC. Nonetheless, further validation on a larger cohort of patients is required.
MAPK pathway alterations as a targetable vulnerability in bladder cancer.
Authors: D'Andrea Vincent , Bekele Raie , Hanlon Timothy , Zhou Yuzhen , Chroneos Rea , Stelter Isabella , Mouw Kent William
Published: January 2024

672

Background: Large-scale genomic studies of bladder cancer (BC) have identified MAPK as a recurrent pathway alteration. The MAPK pathway is a signaling cascade comprising of the proteins RAF, MEK, and ERK, which together control critical cellular processes. Currently, cisplatin-based chemotherapy and anti-PD1/PD-L1 agents are the backbone of systemic therapy in BC, yet only a subset of patients respond. As such, additional novel therapeutic strategies, such as targeting the MAPK pathway, are needed. Herein, we describe the impact of MAPK alterations on BC tumor properties sensitivity to novel MAPK-directed agents. Methods: The activity of the activity of RAF inhibitors (including RAF265 and the novel RAF dimerization inhibitor LXH254) was tested in BC cell lines with diverse MAPK pathway alterations including RAF1 amplification and NRAS mutations. Relative cell viability was measured by luminescence assay following treatment. RAF1-amplified UMUC9 cells were implanted as mouse flank xenografts which were randomized to treatment with vehicle or RAF inhibitor alone or in combination with a MEK inhibitor, trametinib. Mouse weights and tumor measurements were monitored during the treatment period and tumors were excised and weighed. C57BL/6 mice were orthotopically implanted with BBN cells with and without a RAF1 amplification using a surgical approach and tumor volumes were measured under ultrasound (US). Results: RAF1-amplified and NRAS-mutated cell lines demonstrated higher sensitivity to RAF inhibition than non-altered lines. There was a significant reduction in tumor volumes of UMUC9-engrafted mice treated with RAF265 (n=10) or RAF265 plus trametinib (n=8) compared to vehicle controls (n=14). Mice treated with RAF265 alone or with RAF265 plus trametinib had significantly lower tumor weights than vehicle-treated mice. US monitoring showed that mice orthotopically implanted with RAF1-amplified BBN cells (RAF1, n=9) and empty vector cells (EV, n=9) showed take rates [RAF1=67%, EV=78%], mean tumor sizes [RAF1=23.0mm2, EV=12.5mm2, p=0.07], and tumor growth rates [RAF1=0.60mm2/day, EV=0.40mm2/day, p=0.19]. Conclusions: We sought to explore the vulnerabilities incurred by MAPK pathway alterations in BC. We tested the activity of a RAF inhibitors in BC cell lines with RAF1 amplifications and NRAS mutations and found that MAPK pathway-altered models displayed increased sensitivity to RAF inhibition compared to MAPK-unaltered models. We further showed this sensitivity in vivo with RAF1-amplified mouse xenografts and elucidated the synergistic effect of concurrent RAF and MEK inhibition. There was a trend towards larger tumors and more rapid growth rate in orthotopically-implanted RAF1-amplified BC cells compared to controls. Taken together, these data identify MAPK pathway alterations as a novel dependency in BC that may be clinically targeted with small molecule inhibitors.
Longitudinal whole exome sequencing of cell-free DNA in advanced bladder cancer.
Authors: Ravi Arvind , Epstein Ilana , Freeman Dory , Ravi Praful , Coorens Tim , Danysh Brian , Miller Mendy , Leshchiner Ignaty , Hess Julian , Stewart Chip , Riaz Irbaz Bin , McGregor Bradley Alexander , Bellmunt Joaquim , Van Allen Eliezer Mendel , Mantia Charlene , Kilbridge Kerry L. , Clinton Timothy , Mossanen Matthew , Mouw Kent William , Hirsch Michelle S.
Published: January 2024

681

Background: The recent approval of agents from novel therapeutic classes including immunotherapy and antibody-drug conjugates has transformed the treatment landscape of advanced bladder cancer. However, even among patients with initially favorable responses to therapy, a subset of patients develop acquired resistance for reasons that are yet to be fully elucidated. Methods: To gain insight into the dynamics of tumor evolution during the course of treatment, we performed longitudinal profiling of plasma cell-free DNA in a cohort of 71 patients with muscle-invasive or advanced disease before, during, and/or after specific lines of therapy. To further resolve evolutionary dynamics during the course of treatment, we additionally performed Whole Exome Sequencing (WES) on 47 plasma samples across 25 patients. Results: We observed a median tumor purity of 3.8% in the plasma with a range from undetectable (N = 24 samples out of 217 total) to 61%, with tumor purity generally increasing in patients with progressing disease as compared to stable (p = 0.037) or to responding disease (p = 0.002), consistent with the notion that tumor DNA content in the circulation may act as a proxy for overall tumor burden. Phylogenetic reconstruction in 14 patients using WES data identified growing subclones with potential resistance drivers including TP53, PTEN, and FAM46C. In addition, we identified two cases in which growing subclones showed few shared mutations with regressing clones, demonstrating instead largely distinct somatic mutation profiles. Conclusions: Longitudinal WES of cfDNA is feasible in a subset of advanced bladder cancer patients with sufficiently high tumor purity in the blood. In addition, based on our findings of substantial variation in somatic mutations within two reconstructed patient phylogenies, we hypothesize that acquired resistance could in some cases be enabled by marked transitions in the neoantigen repertoire.
AI-based morphologic model for prediction of individual patient response to immune checkpoint inhibitors for bladder cancer.
Authors: Nair Monica , Liao Ross , Jain Parag , Xie Chensu , Muhammad Hassan , Huang Wei , Basu Hirak S , Wilding George , Roy Rajat , Diaz-Montero C. Marcela , Hwang Tae Hyun , Dawsey Scott , Nguyen Jane , Klein Eric A. , Gupta Shilpa , Mian Omar Y.
Published: January 2024

686

Background: Immune checkpoint inhibitors (ICI) have been used to treat advanced muscle invasive and/or metastatic bladder cancer. However, ICIs are only effective in 30-40% of cases. In light of potentially significant IRAE’s, tools to predict individual patient level benefits are desirable. AI technology offers the opportunity to apply computational methods to predict outcomes from readily available digitized pathology slides. We investigated the utility of an AI platform integrating computational biomarkers based on morphological characterization of digitized H&E slide whole images (WSI) to predict response to ICI. Methods: We analyzed H&E-stained whole slide images (WSI) of bladder tumor tissue collected from transurethral resection of bladder tumor (TURBT) from 116 patients with advanced or metastatic bladder cancer at a single institution between 2015-2020. Adjacent multiplex IHC stained specimens were analyzed myeloid and lymphoid marker panels. 20 patients from the overall cohort treated with ICI were designated ‘responders’ (complete response, partial response, stable disease) and 20 patients were identified as non-responders (progressive disease) based on ICI best clinical/radiographic response. WSIs were divided into small non-overlapping image patches. These image tiles were processed into multiple AI encoder models to extract morphological features. The tile morphological features, represented by high dimensional vectors, were combined by an aggregation model to represent the whole slide morphology and then used to classify the patients into responders vs non-responders to immunotherapy. Area-under-the-receiver operating characteristic (AUC) was used to measure the performance of response prediction. Results: Our method shows AUC of 0.708 at classification of the patients (n=40) into responder and non-responder groups. With a cutoff that identifies the top 50% patients (n=20) of high probability of responding to immunotherapy predicted by our models, 75% of them are responders. In the bottom 50% patients (n=20) of the low scores, 75% of them are non-responders. . Multiplex IHC (myeloid and lymphoid panel) was performed using adjacent sections and were characterized yielding deeper mechanistic insight into the inflammatory populations driving predictive morphologic patterns. Conclusions: By applying innovative AI morphological analysis on patient WSIs, we generated a computational biomarker that shows promising ability to predict patient response to immunotherapy in bladder cancer. This approach merits future prospective validation and additional patient level analysis in broader cohorts. [Table: see text]
Dicycloplatin: Assessing the efficacy of a novel platinum analog for treatment of urothelial carcinoma of the bladder.
Authors: Zekan David , Jackson Barbara , Hogan Thomas F. , Kandzari Stanley
Published: January 2024

689

Background: Platinum-based chemotherapies are a component of standard-of-care regimens for urothelial carcinoma (UC). These nephrotoxic drugs are often dose-limiting, with cisplatin and carboplatin most used. Dicycloplatin (DCP) has better solubility and stability, with comparable efficacy and better tolerability. Some suggest use of DCP as primary treatment for non-muscle-invasive bladder cancer. We exposed UC cell lines to DCP in vitro to assess efficacy. Methods: A high grade (IV) in vitro UC cell line (TCCSUP) was exposed to varying concentrations of cisplatin (0-600 ug/mL), carboplatin (0-600 ug/mL), oxaliplatin (0-4.0 ug/mL), and DCP (0-350 ug/mL). Grade II-IV cells were exposed to concentrations of DCP (0-350 ug/mL) to assess time- and concentration-dependence of growth inhibition, and intravesical simulation. Growth inhibition was determined following exposures of 24, 48, and 72 hours using exposure to a tetrazolium dye assessing mitochondrial dehydrogenase activity. Results: DCP, cisplatin, and carboplatin effectively achieved >90% cell-kill at 72 hours. Concentrations of 325 ug/mL DCP, 50 ug/mL cisplatin, and 600 ug/mL carboplatin are sufficient for >90% cell-kill, with cisplatin boasting highest kills at lowest concentration/time intervals. Dose- and time-dependent cell-kill were demonstrated at varying concentrations of DCP in grade II-IV cell lines, including cells exposed in a intravesical fashion. Conclusions: DCP has in vitro cell-kill efficacy in a time- and concentration-dependent manner in grade II-IV UC cell lines, showing promise for its IV, PO, and intravesical use for UC of the bladder in the primary and adjuvant/neoadjuvant setting. Animal studies are forthcoming to assess in vivo efficacy prior to proceeding with clinical trials.
Correlation of artificial intelligence (AI)-based spatial characteristics of tumor-infiltrating lymphocytes outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Hammouda Kamal , Corredor Germán , Pathak Tilak , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Mirtti Tuomas , Gupta Shilpa , Madabhushi Anant
Published: January 2024

691

Background: Quantification of tumor-infiltrating lymphocytes (TILs) in archival hematoxylin and eosin (H&E) specimens of muscle-invasive urothelial cancer (MIUC) specimens can help assess tumor microenvironment (TME) and serve as prognostic and predictive biomarkers to assess outcomes with ICI. There is an unmet need to develop non-invasive computational pathology-based models based on the spatial characteristics of TILs on H&E tissue images for predicting outcomes with ICI in pts with mUC. Methods: We retrospectively analyzed 335 adult pts with mUC treated with ≥2 cycles of ICI with atezolizumab (A) or pembrolizumab (P) at Cleveland Clinic between 2015 and 2023. We used this cohort to validate a prognostic model for bladder cancer (BC) originally trained on the Cancer Genome Atlas (TCGA) dataset. Of the 335 pts in this cohort, we had archival H&E slides from biopsy or radical surgery available for 56 pts (S1). We developed a tumor segmentation model by leveraging the U-net deep learning network. Within the segmented regions, nuclei were segmented and classified into TILs and non-TILs using the HoVer-Net algorithm. Spatial graphs involving the TILs as the nodes of the graphs were constructed and a total of 350 spatial statistics relating to the distances between the TILs and non-TILs were extracted. Using the least absolute shrinkage and selection operator (LASSO) model, the 14 most prognostic features were identified using tissue images from a total of 361 patients with MIBC from the Cancer Genome Atlas (TCGA) (S2). These features were utilized to develop a Cox regression model, aiming to assess the risk of death for individual patients from the S2. The Cox model was then applied to predict risk and outcome for patients from S1. Results: In S2, high-risk patients, as identified by the AI model, had a median overall survival (OS) of 16 months, while low-risk patients had a median OS of 21 months. The model's performance was validated using a blinded dataset from S1, and it showed significant prognostic value for OS in S1 patients, with Hazard Ratio (HR)=1.61 (95% Confidence Interval (CI)=1.18-2.2, and p-value=0.0013). The median OS for the high-risk group based on our model was 26 months and 39 months for the low-risk group, HR 1.90 (95% CI = 0.97-3.73, p-value = 0.036). Conclusions: Computational image features related to spatial architectural patterns of TILs and non-TILs on H&E tissue images correlated with OS in pts with mUC receiving ICI in our real-world cohort. Additional independent multi-site and prospective validation of these findings are warranted.
Development and validation of a novel prognostic model for disease-specific survival in patients with non-metastatic small cell carcinoma of the bladder.
Authors: Diamantopoulos Leonidas Nikolaos , Childs Daniel S , Lewis Akeem Ronell , Lucien Fabrice , Basourakos Spyridon P. , Kase Adam McLain , Singh Parminder , Tyson Mark , Boorjian Stephen A. , Pagliaro Lance C. , Costello Brian Addis , Orme Jacob
Published: January 2024

695

Background: Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with limited data informing prognosis. We present a novel prognostic model for disease specific survival (DSS) for patients with non-metastatic (M0) SCCB, derived from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The SEER database (18 registries/November 2020) was queried with the ICD-10 topography codes C67.0-C67.9 (bladder), and the morphologic code 8041 (SCCB). Eligible patients (adults, histologic confirmation, available follow-up/staging data, M0) were randomly divided into a training (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with DSS were identified with multivariate Cox regression and backwards stepwise conditional approach and inserted in the model. Points were assigned to each variable based on the formula: Probability of an event at time t=S0(t)exp(β1x1, β2x2...), (β = regression coefficients, x = observed covariate values, S0(t) = survival function). Cumulative risk points were assigned to each patient and three distinct risk categories for DSS were constructed. Harrel’s C-statistic with bootstrap resampling was used for internal (TC) and external (VC) validation. Model performance was compared to the AJCC 8th edition (likelihood ratio test -LRT). Results: A total of 1039 patients were included (739 TC, 300 VC). No statistically significant differences in baseline characteristics/survival outcomes were identified between TC and VC. Age (years), T/N stage, radical cystectomy, chemotherapy, and radiation were significant variables inserted in the multivariate model (table). Patients were stratified to three risk groups (low, intermediate, high) based on the total cumulative risk points collected. Median DSS was NR (95%CI; NR, NR), 25 (95% CI; 18-32) and 9 months (95% CI; 7-11) for the low, intermediate, and high-risk category, log-rank p<.001. Harrel's C-statistic for the model was 0.70 (95%CI;0.67-0.73) in the TC and 0.66 (95%CI; 0.61-0.71) in the VC. In comparison, C-statistic for the AJCC 8th edition was 0.56 (95% CI; 0.52-0.59) and 0.53 (95% CI; 0.51 to 0.57), respectively. The LRT demonstrated superior performance of the model compared to AJCC (p<.001). Conclusions: We present a novel prognostic model for DSS in patients with locoregional SCCB composed of variables readily available in daily practice, which may serve as a useful tool for individualized risk assessment of patients with this rare malignancy. Further validation in prospective studies/clinical trials is warranted. [Table: see text]
Platinum eligibility (PE) criteria for patients with metastatic urothelial carcinoma (mUC): Results of a physician survey in 5 European countries.
Authors: Gupta Shilpa , Powles Thomas , Kearney Mairead , Panattoni Laura , Land Natalie , Flottemesch Thomas , Sullivan Patrick , Kirker Melissa , Bharmal Murtuza , Guenther Silke , Costa Nuno , Grande Enrique
Published: January 2024

696

Background: The standard of care for mUC is platinum-based chemotherapy (PBC) followed by avelumab first-line (1L) maintenance in patients without disease progression. Guidelines for mUC recommend 1L treatment based on eligibility for PBC (cisplatin or carboplatin), but the definition of PE remains unclear, and little is known about criteria used by European physicians to define PE in clinical practice. In this cross-sectional study, we assessed treatment decision-making factors and clinical thresholds used by European physicians determine PE and examined their alignment with published US physician thresholds. Methods: Physicians from France, Germany, Italy, Spain, and the UK completed a quantitative online survey in Aug/Sep 2022. We adapted Gupta et al’s ASCO-GU 2019 and ASCO 2022 US-based surveys, which identified thresholds for clinical criteria used by US physicians to define PE. This EU survey included clinical parameters with different age and creatinine clearance (CrCl) thresholds, plus Eastern Cooperative Oncology Group performance status (ECOG PS) and other relevant criteria. Participants reported the percentage of patients they perceived were platinum eligible and ranked criteria to determine PE. All analyses used descriptive statistics. Results: 503 physicians (69% oncologists, 31% urologists) completed the quota-based survey. Most had been in practice for >10 years (69%), treated 5-19 patients with mUC per month (58%), and practiced in a public teaching hospital (40%). Most patients who received 1L systemic treatment were PE (77%), ranging from 75% in Italy to 79% in Spain. Most respondents chose >80 years (33.2%) or >75 years (24.1%) as the age threshold for platinum ineligibility. Age thresholds selected were significantly different across countries, years of practice, and practice settings (p<0.001). Responses for ECOG PS and peripheral neuropathy thresholds for platinum ineligibility were evenly split between ECOG PS ≥2 (40.6%) and ≥3 (45.3%) and between grade ≥2 (44.3%) and ≥3 (41.7%) peripheral neuropathy. The most frequent responses are summarized (Table). Conclusions: Physicians in Europe considered most patients with mUC to be platinum eligible. Criteria to determine PE were broadly consistent with previous US-based studies, except for age. The low age threshold observed is at odds with the older age of the mUC patient population. Wider use of these criteria could support clinical decision-making, reduce variations in care, and improve patient outcomes. [Table: see text]
Testosterone suppression and recovery in patients with advanced prostate cancer treated with intermittent androgen deprivation therapy (iADT) with relugolix.
Authors: Campbell Patrick , Gebrael Georges , Narang Arshit , Hage Chehade Chadi , Mathew Thomas Vinay , Galarza Fortuna Gliceida , Sayegh Nicolas , Tripathi Nishita , Tandar Clara , Dal Emre , Li Haoran , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: January 2024

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Background: Many patients with advanced prostate cancer do not want to pursue continuous androgen deprivation therapy (cADT) because of concerns about side effects, and pursue iADT. However, even intermittent treatment with GNRH agonist therapy may not lead to rapid recovery of testosterone during the off-treatment period. In the pivotal HERO trial of relugolix (GNRH antagonist) the testosterone recovery time was in weeks [PMID 32469183]. The objective of the study was to measure the time to testosterone suppression to castrate level and time to recovery of serum testosterone to non-castrate level in real-world patients with advanced prostate cancer undergoing intermittent relugolix therapy. Methods: In this IRB-approved retrospective study, the eligibility was: patients with advanced prostate cancer undergoing iADT with relugolix. iADT with relugolix was defined as initiating relugolix at PSA ≥ 10 ng/ml and holding relugolix when PSA ≤ 4 ng/ml. The primary endpoints were: 1) time to serum castrate level of testosterone after relugolix initiation and 2) time to recovery to non-castrate level after discontinuation of relugolix. Castrate level of serum testosterone was defined as serum testosterone level ≤ 50 ng/dL. Results: Overall 25 consecutive patients with advanced prostate cancer treated with iADT with relugolix were eligible and included. The median age was 75 [range 68-88]. Patients with a Gleason score of ≥ 8 comprised 44% of the cohort. The median PSA at the start of therapy was 18.2 ng/ml [5.1 – 99.1 ng/ml]. Median time to testosterone ≤ 50 ng/dl after relugolix initiation was 1.13 months [0.67 – 2.5 months], and median time to testosterone recovery after relugolix discontinuation was 1.4 months [0.83 – 6.57 months]. The median PSA nadir achieved with relugolix was 2.02 ng/ml [0.1 – 4.8], and median time to PSA nadir was 1.35 months from initiation of therapy (0.67 – 4.8 months). Median time to PSA relapse ≥ 10 ng/dl after holding relugolix was 3.4 months (0.9 – 8.23 months). Conclusions: This is the first real-world study to show that iADT with relugolix is associated with a rapid time to testosterone suppression and recovery. These results may guide patients’ counseling, monitoring of serum testosterone and PSA levels in patients wishing to pursue iADT for advanced prostate cancer. These hypothesis-generating data need external validation.
Risk factors for neoadjuvant chemotherapy-induced acute kidney injury in patients with muscle-invasive bladder cancer: A multicenter retrospective study.
Authors: Fujita Naoki , Momota Masaki , Tanaka Toshikazu , Hosogoe Shogo , Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara
Published: January 2024

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Background: Neoadjuvant chemotherapy (NAC)-induced acute kidney injury (AKI) is one of the frequent complications in patients with muscle-invasive bladder cancer (MIBC) and we previously have reported the negative impact of NAC-induced AKI on oncological outcomes. However, its risk factors remain unclear. Methods: This multi-institutional retrospective study included 517 patients with MIBC who received 2–4 cycles of NAC followed by radical cystectomy. AKI was defined according to the KDIGO criteria. Patients were divided into two groups: patients who developed any stage AKI during NAC (AKI group) and patients who did not (non-AKI group). Multivariable logistic regression analysis was performed to identify the risk factors for NAC-induced AKI. The predictive abilities for AKI were evaluated using the area under the receiver operating characteristic curve. Results: The median age was 69 years. Of the 517 patients, 188 (36%) received cisplatin-based regimens and 92 (18%) developed any stage AKI. Approximately 86% AKI were stage 1 AKI. In the univariable analyses, hypertension, impaired renal function, and cisplatin-based regimen were significantly associated with increased risk of AKI. In the multivariable analysis, hypertension, impaired renal function, and cisplatin-based regimen were independently and significantly associated with increased risk of AKI (Table). The optimal cutoff value of estimated glomerular filtration rate for AKI was 65.0 mL/min/1.73m2. ROC analysis showed that the AUC of hypertension plus eGFR <65.0 mL/min/1.73m2 plus cisplatin-based regimen was 0.748 (95% confidence interval [CI]: 0.697–0.799]. Conclusions: Hypertension, impaired renal function, and cisplatin-based regimens were risk factors for NAC-induced AKI in patients with MIBC. [Table: see text]
Does use of apalutamide enhance outcomes in combination with radiotherapy in metastatic hormone-sensitive prostate cancer? A real-world experience from the UK.
Authors: Das Prantik , Sharma Anand , Vengalil Salil , Khan Yakhub , Lim JunHao , Elmasry Abdelfattah , Mohammed Rania , Ghose Aruni , Bandyopadhyay Seheli , Nillegoda Hasanthi , Baraka Bahaaeldin , Tasmia Syeda , Mathiyalagan Navin
Published: January 2024

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Background: Management of metastatic prostate cancer has undergone a significant change over the past decade, with the introduction of several novel agents and repurposing of others. Latest update from STAMPEDE trials shown prostate radiotherapy (RT) improves OS, without detriment in QoL in metastatic home sensitive prostate cancer mHSPC along with Docetaxel in those with low volume metastatic disease. There is no published data on impact of radiotherapy to prostate on Apalutamide treated mHSPC patients. Here we report our real-world experience of Apalutamide in mHSPC with radiotherapy. Methods: Patients with mHSPC (N = 266) from 5 UK centres, were treated with Apalutamide (240 mg) and ADT along with radiotherapy to prostate as per treating clinician’s discretion. The primary endpoint was objective rate (ORR) as determined by patients achieving a PSA decline of ≥90% (PSA90) and ≥50% (PSA50) and secondary endpoints included biochemical progression free survival (bPFS) and safety. Results: The median age for the whole cohort was 73.4 years (interquartile range 52 - 91), A total of 11.6% had received prior radical treatment (prostatectomy or radiotherapy for localised disease) and 88.4% had de novo metastatic disease. Median baseline PSA was 47 ng/ml (range 0.4-17100). The proportion of patients PSA90 and PSA50 at 3, 6 and 12 months is shown in the Table. Median PSA nadir was 0.1 ng/ml(rage 0.01- 48.2) and median time to reach nadir was 6 months (range 3-24 months). 13.5% (35) patients were treated with radiotherapy (RT) after at least 3 months (range 3 -6 months) of starting apalutamide. Patients received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) of radiotherapy (68 % vs 32%). Higher number of patients in RT group had achieved PSA90 compared to no radiotherapy cohort (97.14 % vs 87.3%, p =0.15). Patients treated with RT had median post treatment of PSA 0.01 ng/ml compared to 0.1 ng/ml in non RT group (p=0.0062). After median follow up of 8.4 months, proportion of patients shown biochemical progression in RT vs non RT group were 5.7 % vs 15 % respectively (p= 0.04). Patients with de novo metastatic disease have shown poor PSA response and higher chance of progression compared to patients who had initial radical treatment. Radiotherapy was well tolerated, with 17 % adverse events (Radiation Therapy Oncology Group grade 3–4) reported in radiotherapy group. Conclusions: Early experience of using apalutamide and radiotherapy in mHSPC showed improved PSA response and delayed progression. Treatment was well tolerated. Further follow up and clinical trials are needed to understand the impact on overall survival. [Table: see text]
Cardiovascular medications and overall survival in metastatic hormone-sensitive prostate cancer.
Authors: Ingram Kara , Pickett Carley , Eaton Daniel B. , Tohmasi Steven , Karunanandaa Krishny , Gopukumar Deepika , Puri Varun , Schoen Martin W.
Published: January 2024

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Background: The assessment of comorbid cardiovascular disease can predict health outcomes and may risk-stratify patients for adverse events and death. Current methods used to estimate patient risk, such as the Charlson Comorbidity Index (CCI), are based on International Classification of Diseases (ICD) codes, which are a poor indicator of severity and complexity of comorbid disease. Alternatively, the number of cardiovascular drugs could be an efficient tool for estimating patient risk. In this study, we examined the relationship between cardiovascular medications and survival in patients being treated for metastatic hormone-sensitive prostate cancer (mHSPC). Methods: A nationwide retrospective observational study of US Veterans with de novo mHSPC in the Veterans Health Administration between 2011-2021 with at least 1 prescription medicine of any class. We determined the number of cardiovascular drugs from Anatomic Therapeutic Chemical (ATC) drug class C prescribed in the year prior up to 14 days before initiation of treatment. Multivariable logistic regression and Cox proportional hazard modeling was used to assess the association between number of drugs with overall survival (OS) while accounting for important covariates including age, body-mass index (BMI), prostate specific antigen (PSA), CCI, race, and weight change. Results: Among 7,875 veterans, a median (IQR) of 2 (1-4) unique cardiovascular medications were filled in the year prior to treatment. The mean age was 74.3 years (SD 10.0) with a median CCI of 3 (3-6). Age was associated with increased number of cardiac medicines with a mean of 1.6 drugs in <60 years, 2.2 drugs in 60-69, 2.5 drugs in 70-80, and 2.5 drugs in 80+ years (p<0.001). Increased number of medications was associated with decreased OS using the Kaplan-Meier method (p<0.001, see table). After adjusting for age, race, BMI, weight change, PSA, and CCI, the number of medications was independently associated with increased mortality with an adjusted hazard ratio (aHR) of 1.05 (1.03-1.06) for each additional cardiac drug. Increased mortality was observed in patients treated with 2 or more cardiac drugs (see table). Conclusions: The number of cardiovascular medications is associated with decreased survival in veterans undergoing treatment for mHSPC, even after accounting for important covariates including age, BMI, PSA, and CCI. The assessment of cardiovascular medications may provide a simple and reliable tool to estimate comorbid disease and survival in patients with cancer. [Table: see text]