bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of PD-L1 and B7-H3 expression as a predictor of response to adjuvant chemotherapy in bladder cancer.
Authors: Mahmoud Ahmed , Frank Igor , Ahmed Mohamed E. , Orme Jacob , Lavoie Roxane , Thapa Prabin , Costello Brian Addis , Cheville John , Gupta Sounak , Dong Haidong , Lucien Fabrice 
Published: March 2023

548 Background: PD-L1 and B7-H3 have been found to be overexpressed in urothelial carcinoma (UC) of the urinary bladder. Recent studies have also demonstrated that B7-H3 and PD-L1 can promote resistance to platinum-based drugs but the predictive value of B7-H3 expression in patients treated with platinum-based chemotherapy is unknown. This study aims to investigate the association of PD-L1 and B7-H3 tumor expression with oncological outcomes in patients who underwent radical cystectomy (RC) and received subsequent adjuvant chemotherapy. Methods: Immunohistochemistry was performed on paraffin-embedded sections from bladder and lymph node specimens of 81 patients who had RC for bladder cancer. PD-L1 and B7-H3 expression on tumor cells was assessed by immunohistochemistry in both primary tumors and lymph node specimens. Association with clinicopathologic outcomes was determined using Fisher’s exact test and postoperative survival using Kaplan–Meier survival curves and Cox regression model. Results: B7-H3 expression in cystectomy specimens was more common than PD-L1 expression (72.8% vs. 35.8%). For both markers, no association was found with pathologic tumor stage, lymph node (LN) status, and histological subtype. Similar findings were observed for double-positive tumors (PD-L1+B7-H3+). Concordance between the primary tumor and patient-matched lymph nodes was found in 76.2% and 54.1% of patients for PD-L1 and B7-H3, respectively. PD-L1 tumor expression was not associated with oncologic outcomes. However, B7-H3 expression was associated with recurrence-free survival (HR: 2.38, 95% CI 1.06–5.31, p = 0.035) and cancer-specific survival (HR: 2.67, 95% CI 1.18–6.04, p = 0.019). Conclusions: In our single institutional study, B7-H3 is highly expressed in patients with UC treated with adjuvant chemotherapy and it was associated with decreased recurrence-free survival and cancer-specific survival. Pending further validation in larger cohorts, B7-H3 expression may function as a predictor of response to adjuvant chemotherapy and thus be useful in patient and regimen selection.
Distinct gene expression patterns identify patients who relapse after neoadjuvant pembrolizumab and radical cystectomy in the PURE-01 study.
Authors: Reike Moritz Johannes , Raggi Daniele , Marandino Laura , Patanè Damiano Alfio , Crupi Emanuele , Padua Tiago Costa de , Black Peter C. , Gibb Ewan , Necchi Andrea 
Published: March 2023

549 Background: The PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC; cT2–3N0M0; PMID 30343614). We have previously reported that specific molecular subtypes (i.e. basal or claudin-low) and immune signatures are associated with more favorable survival. However, reports on the detailed tumor biology of patients (pts) who relapsed after neoadjuvant pembrolizumab are lacking. Herein, we provide a detailed characterization of relapsing pts and identify distinct gene expression patterns with potential utility as novel biomarkers. Methods: Microarray data from transurethral resection of the bladder tumor (TURBT; N=102) and matched RC (N=25) tissue from the PURE-01 trial were analyzed. Gene expression signatures and molecular subtypes were assigned as previously described (PMID 32165065). The Kaplan-Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of 0.05. Results: Differential gene expression analysis identified KRT20 and H19 to be enriched in relapsing patients (both p<0.001). Expression below the median was predictive of favourable 3-year overall (OS) and recurrence-free (RFS) survival (OS, 37.3% vs. 21.6%, p=0.118; RFS, 35.3% vs. 21.6%, p<0.01 and OS, 41.2% vs. 17.6%, p=0.03; RFS, 39.2% vs. 17.6%, p=0.012, respectively). Distribution of molecular subtypes showed tumors with neuronal character (NE-like) were enriched in pts who relapsed. Low immune-signatures, including Interferon-gamma and -alpha, were predictive of relapse (3-year RFS, 31.4% vs. 25.5%, p<0.001 and 31.4% vs. 25.5%, p<0.01, respectively), whereas Immunophenoscore for CD4 was not. None of these markers were predictive for relapse in matched RC-samples. Conclusions: Relapsing patients demonstrated distinct biological patterns in pre-therapy tumor samples that show prognostic value, potentially making an earlier identification and therefore adapted treatment possible. Low expression of immune-related signatures was associated with relapse.
Complimentary genomic, pathologic, and artificial intelligence analysis on low-grade noninvasive bladder cancer to predict downstream recurrence.
Authors: Rose Kyle M. , Vosoughi Aram , Borjas Gustavo , Huelster Heather L , Spiess Philippe E. , Berglund Anders E. , Sexton Wade J. , Joshi Anirudh , Kumar Nagi B. , Li Roger 
Published: March 2023

553 Background: Low-grade noninvasive (LGTa) bladder cancer is a relatively quiescent but heterogenous malignancy, characterized by downstream recurrences requiring repeated transurethral resections and frequent surveillance. Investigations to elucidate drivers of recurrence have been sparse, but will help risk-stratify patients with LGTa and allow augmentation of follow up protocols. Methods: Patients with LGTa index tumors were stratified by those with no downstream recurrences (nonrecurrent) vs. those with later recurrences (recurrent). RNA sequencing identified differentially expressed genes (DEGs), deconvoluted for cell-type using xCell. Pathologic analysis was performed by a genitourinary pathologist, then a deep-learning artificial intelligence (AI) platform was leveraged to correlate recurrence risk and recurrence-free survival (RFS) based on deep-learning algorithm of segmented nuclei. Results: Thirty index bladder tumors/patients were identified, 18 (60%) of which had later recurrence (Table). There were 238 DEGs recognized, with recurrent tumors expressing signatures for epithelial mesenchymal transition, myogenesis, TNFα signaling via NFκB, and angiogenesis. Recurrent tumors also demonstrated a higher tissue micoenvironment, stroma, and cancer-associated fibroblast score. Pathologic TME analysis validated these findings, with recurrent tumors demonstrating a higher frequency of inverted growth pattern and a higher median stroma percentage. Finally, the AI-derived signature was predictive of recurrence and risk-stratified the cohort (HR= 5.43 [95% CI 1.1-26.76]) for predicting high vs. low risk of recurrence. Patients in the high risk group had a 87.5% recurrence rate while those in the low risk group had a 28.5% recurrence rate (p<0.01). Conclusions: Using a multi-disciplinary approach, we identified key signatures in recurrent LGTa bladder cancer. Characterization of these factors is a critical first step in the risk-stratification of LGTa tumors, and may allow risk-stratification of surveillance protocols and identification of possible targets for chemoprevention trials. [Table: see text]
Associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 with molecular subtypes, PD-L1 expression and FGFR3 mutational status in two advanced urothelial bladder cancer cohorts.
Authors: Bahlinger Veronika , Branz Annalena , Strissel Pamela , Strick Reiner , Lange Fabienne , Geppert Carol-Immanuel , Klümper Niklas , Hölzel Michael , Wach Sven , Taubert Helge , Sikic Danijel , Wullich Bernd , Angeloni Miriam , Ferrazzi Fulvia , Diehl Lauri , Kovalenko Maria , Elboudwarej Emon , Juergensmeier Juliane Margarete , Hartmann Arndt , Eckstein Markus 
Published: March 2023

554 Background: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved in recent years. Besides immunomodulative therapeutic options like anti-PD-(L)1 inhibitors and inhibitors targeting FGFR alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved for treatment. However, little is known about associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. This study characterizes associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 gene and protein expression with morphomolecular and clinico-pathological characteristics of aUC in two large independent cohorts. Methods: The TCGA BLCA (n=405) and the CCC-EMN (n=247) cohorts were retrospectively analyzed. Expression of mRNA and protein for TACSTD2/TROP2 and NECTIN-4/NECTIN-4 was measured and correlated with clinico-pathological characteristics, molecular subtypes, FGFR3 alterations and PD-L1 expression. Results: TACSTD2/TROP2 and NECTIN-4/NECTIN-4are highly expressed at protein and transcript level in aUC, and their expression status did not correlate with patient survival in two independent cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumors and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-Score < 15). TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double negative tumors. TROP2 and NECTIN-4 negative tumors (protein level) included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumor and immune cells did not associate with TROP2 or NECTIN-4 expression. Conclusions: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression. Expression loss is associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC. TROP2 and NECTIN-4 are widely expressed in aUC thus representing suitable targets for novel ADC treatment for the majority of aUC patients.
Characterization and impact of Wnt5A signaling on outcomes of urothelial carcinoma.
Authors: Salmasi Amirali , Krause Harris , Elliott Andrew , Farrell Alex Patrick , Antonarakis Emmanuel S. , Bastos Bruno R. , Heath Elisabeth I. , Jamieson Christina , Stewart Tyler F. , Bagrodia Aditya , Nabhan Chadi , Oberley Matthew James , Korn W. Michael , McKay Rana R. 
Published: March 2023

560 Background: Active Wnt signaling via WNT5A through ROR1 and its partner, ROR2, or WNT5A/frizzled 2 (FZD2) is linked to processes driving tumorigenesis, disease progression and therapy resistance. The role of this pathway in the pathogenesis of urothelial carcinoma (UC) is not fully elucidated. In adult tissue, ROR1 is largely absent, which makes it ideal for targeted therapies, with several ROR1 targeting agents in early clinical development. We utilized a large dataset of molecularly characterized UC tumors to investigate the significance of Wnt5a/ ROR1, ROR2 or FZD2 transcriptional expression. Methods: NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4743 UC tumors submitted to Caris Life Sciences (Phoenix, AZ). PD-L1 expression (SP142; Positive (+): ³2+, ³%5) was tested by IHC. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed; Bao, 2020). WNT5a, ROR1, ROR2, and FZD2-high and -low expression were defined as ³ top and < bottom quartile of transcripts per million (TPM), respectively. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( q < .05). Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan Meier estimates were calculated for molecularly defined cohorts. Results: We observed similar expression of these WNT5A signaling pathway genes between upper (N=795) and lower tract UC (N=3,204): WNT5A (22.7 v. 22.2 median TMP (mTPM), q = .18), FZD2 (3.4 v 3.5, q = .93), ROR1 (2.0 v. 1.7, q = .05), and ROR2 (2.1 v 2.5, q < .01). WNT family gene expression varied significantly between primary (N=2,756) and metastatic sites (N=1,361): WTN5A (25.2 v 16.8 mTPM), FZD2 (3.2 v 4.05), ROR1 (1.7 v 2.1), and ROR2 (2.4 v 2.6) for primary vs. metastatic sites respectively ( q < .05 for all). Comparison of high- and low-expression subgroups revealed variation in the prevalence of TP53, FGFR3 and RB1 mutations, as well as PDL1+ staining and T cell-inflamed scores (Table). High gene expression for ROR2 (HR 0.66, 95% CI 0.56-0.78, p < .001) and FZD2 (HR 0.75, 95% CI 0.63-0.89, p < .001) was associated with worse OS compared to low gene expression. No significant difference in OS was observed for WNT5A (HR 0.97, 95% CI 0.82-1.15, p < .76) and ROR1 (HR 0.86, 95% CI 0.72-1.01, p < .068). Conclusions: Distinct genomic and immune landscapes for the four investigated WNT pathway components were observed and should be leveraged to identify combination therapies that complement the current pipeline of WNT pathway-targeting drugs. [Table: see text]
Characterization of the tumor transcriptomic differences by smoking history in locally advanced or metastatic urothelial carcinoma (UC).
Authors: Sahu Kamal Kant Kant , Tripathi Nishita , Chigarira Beverly , Sayegh Nicolas , Mathew Thomas Vinay , Li Haoran , Jo Yeonjung , Gebrael Georges , Iyer Puja , Nussenzveig Roberto , Agarwal Neeraj , Maughan Benjamin L. , Gupta Sumati , Swami Umang 
Published: March 2023

561 Background: Understanding the influences of cigarette smoke exposure at the gene expression level may have clinical significance and therapeutic implications. Investigating variations in the gene expression patterns could provide insights into differences in disease progression, survival, and therapeutic response based on smoking history amongst smokers vs. non-smokers (PMID: 29050337). Our objective was to correlate smoking with the gene expression of pts with locally advanced or metastatic UC. Methods: In this IRB-approved retrospective study, eligibility criteria included pts with locally advanced or metastatic UC with available tumor-based comprehensive transcriptomic profiling from a CLIA-certified lab. DeSeq2 analysis was implemented in Bioconductor software to analyze differentially expressed genes based on smoking history. DeSeq2 results included the Log2 Fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were then subjected to Gene Set Enrichment Analysis (GSEA) to identify pathways upregulated or downregulated in each cohort. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Statistical significance was predetermined at p < 0.05. Results: 38 pts were eligible and included: Smokers (n=18) and non-smokers (n=20). The median age at diagnosis for smokers vs. non-smokers (67 vs.71 years). The three most upregulated significant pathways amongst smokers (vs. non-smokers) were the MYC, E2F target, and cholesterol homeostasis pathways (q for all <0.01) [Table]. The three most downregulated significant pathways were interferon-alpha, interferon-gamma, and inflammatory response pathways (q for all <0.01). Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with advanced UC with smoking history demonstrated a different transcriptomic profile than those without smoking. Increased expression of proto-oncogene MYC and E2F could explain an aggressive disease amongst smokers. Future trials could utilize these transcriptomic differences by smoking history in guiding drug development. These hypothesis-generating results, upon external validation, may provide the rationale for personalized therapy in pts with UC. [Table: see text]
Oncologic outcomes following post-cystectomy recurrence of bladder cancer based on metastatic site and role of salvage immunotherapy.
Authors: Ladi Seyedian Seyedeh Sanam , Doshi Chirag , Santos Molina Luis , Wood Erika , Cai Jie , Miranda Gus , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak 
Published: March 2023

574 Background: To evaluate how the location of bladder cancer recurrence after radical cystectomy (RC) affects survival and assess the role of salvage immunotherapy in this setting. Methods: On retrospective review of 4093 patients from our institutional IRB approved cystectomy database from January 1971 to December 2021, we identified 889 patients who underwent RC with curative intent and have been detected with recurrence of bladder cancer. Patients with urethral and ureteral recurrence were excluded. The data was then stratified based on the site of recurrence. Results: In this cohort of 889 patients (median age of 68, 77% male), the most common sites of metastases were widespread (48%), local (15%), lung (10%), bone (8%), retroperitoneal nodes (5.5%), liver (5%) and brain (1.5%) in order. With a median of 8.4 months, bone metastasis had shortest length from cystectomy to recurrence, while liver metastasis had shortest post recurrence survival (median of 4 months). For distant recurrence alone, only 33% survived past the first year. Salvage immunotherapy was administered in 8% of the patients and 47% received salvage chemotherapy. On multivariate analysis, liver metastasis (HR 2, 95%CI 1.4-2.9), widespread metastasis (HR 1.9, 95%CI 1.5-2.4), pathological staging>T3 (HR 1.3, 95%CI 1.1-1.6) and nodal involvement at the time of RC (HR 1.5, 95%CI 1.2-1.7) were significantly associated with worse survival after the recurrence. Salvage immunotherapy provided a significant improvement in post-recurrence survival (HR 0.2, 95% CI 0.1-0.3). Conclusions: Liver, brain, and widespread metastases predominantly showed the lowest chance of survival past one year from recurrence; however, more than half of all patients with recurrence did not live past the first year. Salvage immunotherapy may lead to a better prognosis in recurrence post-cystectomy. [Table: see text]
Prognostic value of C-11 choline PET/CT scan in patients with metastatic castration resistant prostate cancer (m-CRPC) undergoing treatment with radium-223.
Authors: Lee Matthew , Ahmed Mohamed E. , Kwon Eugene D. , Kendi Ayse T. 
Published: March 2023

59 Background: Radium-223 (Ra-223) has been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with predominantly osseous metastases. PSA flare phenomenon with Ra-223 limits the use of PSA as a prognostic tool to predict treatment response. Currently, there is a lack of diagnostic tools to predict treatment response to Ra-223. Therefore, we sought to investigate the role of mid-treatment C-11 choline PET/CT scan in predicting overall response to Ra-223. Methods: In a single institute retrospective study, we identified 32 patients who were treated with a full course of 4-6 cycles of Ra-223 and were evaluated with both PSA and C-11 choline PET scan before treatment, at mid-treatment, and after a complete course of Ra-223 between 2013 – 2018. Ra-223 was used as salvage therapy for their predominant bone disease after failing chemotherapy and 2nd generation hormone therapy. Blind repeat radiographic evaluation of patients’ scans was performed by a radiologist specialized in nuclear radiology. Favorable response was defined by achieving partial response or stable disease on imaging, while unfavorable response was defined by showing progressive disease on imaging. Results: Mean age (±SD) at starting Radium223 was 67.6 (±7.1) years, median (IQR) primary Gleason score was 9 (8-9), and median (IQR) pretreatment PSA was 13.5 (5.4-39.6) ng/ml. 78% of the patients (n=25) completed 6 cycles of Ra-223, 15% of the patients (n=5) completed 5 cycles, and 6% (n=2) received only 4 cycles. At mid-treatment scanning, 25% of the patients (n=8) showed favorable response (Group A), while 75% of the patients (n=24) showed unfavorable response (B). After a complete course of treatment, 62.5% of patients (n=5) in Group (A) continued to show favorable response, while only 8.3% of patients (n=2) in Group (B) showed favorable response (p-value= 0.0023). Conclusions: Mid-treatment evaluation with C-11 choline PET/CT scan can predict overall response to Radium 223. Patients with progressive disease at mid-treatment evaluation are very likely not going to respond to further treatment. Further studies and clinical trials are warranted.
Factors associated with poor survival outcomes in patients with prostate cancer (PCa) with radiographic disease progression in the setting of low PSA.
Authors: Ahmed Mohamed E. , Mahmoud Ahmed , Andrews Jack R. , Lee Matthew , Childs Daniel S , Kendi Ayse T. , Johnson Geoffrey , Tollefson Matthew K. , Boorjian Stephen A. , Karnes R. Jeffrey , Kwon Eugene D. 
Published: March 2023

60 Background: Recent studies, including a post-hoc analysis of the ARCHES trial, highlight radiographic disease progression (rDP) occurring without concordant rise in prostate specific antigen (PSA). In a previous study by our group, we reported that almost 40% of patients on 2nd generation hormone therapy experience rDP with non-rising PSA and have poor survival outcomes. The current analysis more specifically focuses on the subgroup of patients with rDP occurring at low PSA (<0.5 ng/dL) and describes factors associated with poorer survival outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET registry for patients treated between 2011 and 2021, who experienced rDP at low PSA (value < 0.5 ng/mL). Disease progression on C-11 choline PET was confirmed by either tissue biopsy or subsequent response to therapy. We investigated factors associated with poor cancer-specific survival outcomes in univariable and multivariable cox regression analyses. Results: In total, 220 (16%) patients experiencing rDP at low PSA were identified. Median (IQR) age at rDP was 67.91 (61.10 – 73.87) yrs., median (IQR) primary Gleason score was 9 (7-9), and median (IQR) PSA was 0.17 (0 – 0.32) ng/ml. 75% of the patients (n=166) had CRPC disease status at time of rDP. Prior systemic treatments included 2nd generation HT in 18% (n= 40) and chemotherapy in 31% (n=70). Sites of rDP were divided into 7% local (n=16), 42% lymph nodes (n=91), 43% bone (n=95), and 8% visceral metastases (n=18). Over a median follow-up duration of 55 months, 46% of patients (n=100) reported death. Factors associated with poor survival outcomes are demonstrated in the table and include age at rDP, CRPC status, and disease location (P-value <0.05). Conclusions: We found that radiographic disease progression commonly occurs at low PSA (<0.5 ng/mL). CRPC-disease status and the development of visceral metastases are associated with particularly poor survival outcomes. To identify early progression, monitoring with imaging may be warranted, even in the patients with low PSA. [Table: see text]