bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing immune-genomic signatures associated with response to immune checkpoint inhibitors (ICI) in patients with metastatic urothelial carcinoma (mUC).
Authors: Pramod Nikhil , Dawsey Scott , Pavicic Paul G. , Lodha Roshan , Patgunarajah Ubenthira , Nair Monica , Ornstein Moshe Chaim , Gilligan Timothy D. , Wee Christopher Eing , Mian Omar Y. , Nizam Amanda , Nguyen Jane , Diaz-Montero C. Marcela , Gupta Shilpa 
Published: June 2023

e16582 Background: Response rates with ICI are modest at around 20% in mUC and there is a lack of validated biomarkers to select pts who are likely to derive benefit from ICI. There is an unmet need to develop biomarkers of response and resistance to avoid unnecessary treatment (Tx) and spare physical and financial toxicity. Here we report tumor immune-genomic characteristics associated with response and resistance to ICI in mUC. Methods: We selected 58 mUC pts who received at least 2 cycles of ICI (atezolizumab or pembrolizumab) between 2015-2020 and had pre-Tx archival formalin fixed paraffin-embedded (FFPE) tissues available. Pts were categorized by their response to ICI as responders (R) (Complete Response (CR), Partial Response (PR), and Stable Disease (SD)) (N = 30) or non-responders (NR) (Progressive Disease (PD)) (N = 28). Tumor was macrodissected from FFPE slides and RNA extraction was done using Qiagen Rneasy FFPE kit. 100ng of RNA was used for transcriptomic analysis using the Nanostring PanCancer IO 360 panel. Data normalization and analysis was carried out using nSolver 4.0. Results: Differential expression analysis comparing (R) vs (NR) displayed upregulation of gene signatures associated with Immunoproteasome, Antigen presenting machinery (APM), IFN Gamma, PD-L1, and IFN downstream. Additionally, the tumor inflammation signature (TIS), which is trained to predict response to ICI, was upregulated in (R) vs (NR) (Table 1). Single gene analysis showed trend towards upregulation of ISG15 (logFC = 0.7821, p = 0.00337), TAP1(logFC = 0.7649, p = 0.00422), and STAT1 (logFC = 0.6053, p = 0.00510) in (R), P-values, were above significance threshold after adjustment for multiple comparisons. Receiver operator characteristic (ROC) analysis with area-under the curve (AUC) scores assess capacity of gene signatures to predict response to ICI (Table 1). In our cohort, the median overall survival for (R) was 44.1 months compared to 24.5 months in NR (p = 0.0100). Conclusions: In our cohort of mUC pts treated with ICI, we found an association between signatures of tumor immunogenicity (APM and Immunoproteosome) and anti-tumor immune activity (IFN Gamma, IFN Downstream, TIS) in pre-Tx tissue with favorable response to therapy (including SD). These findings are hypothesis generating and need to be further validated in prospective trials. Ongoing genomic and immunologic correlative studies in our cohort will further help understand comprehensive biomarkers of response and resistance to ICI in pts with mUC. [Table: see text]
Immune checkpoint inhibitors therapy in advanced bladder carcinoma: A meta-analysis of phase III randomized controlled trials.
Authors: Patel Rushin , Chitkara Akshit , Patel Zalak , Patel Mrunal , Anamika Fnu , Trivedi Shivang , Ramaswamy Bhuvaneswari 
Published: June 2023

e16584 Background: Currently, platinum-based chemotherapy is the standard treatment for advanced bladder cancer. Immune checkpoint inhibitors (ICIs) have been evaluated in these patients with clinical trials. There is no meta-analysis available of phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in these patients. In this article, we write about the meta-analysis of ICIs use in advanced bladder cancer. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google scholar, and ClinicalTrials.gov were searched for relevant studies with prespecified terms. We included only phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in patients with advanced bladder carcinoma. Outcomes studied were Overall survival (OS), Progression-free survival (PFS), Objective response rate (ORR), and Grade 3 or higher adverse events (AE). We used a random effects model via RevMan 5.4 software to perform the meta-analysis. Results: 8 phase III RCTs met the inclusion criteria with a total of 5041 patients (immune checkpoint inhibitors = 2481 patients, Chemotherapy/placebo = 2560 patients) and a median follow-up of 24 months. Compared to the chemotherapy/placebo group, immune checkpoint inhibitors showed higher OS [HR = 0.83 (0.73-0.93) P = 0.002]. No significant differences were observed in PFS [HR = 0.84(0.68-1.05) P = 0.13] and ORR [HR = 2.15(0.51-9.09) P = 0.30] between the two groups. Compared to the chemotherapy group, immune checkpoint inhibitors showed significantly fewer severe adverse events [HR = 0.21 (0.14-0.32) P < 0.00001]. Conclusions: The use of immune checkpoint inhibitors in patients with advanced bladder carcinoma is associated with favorable overall survival and fewer severe adverse events. The two groups observed no significant differences between progression-free survival and objective response rates.
Radiogenomics of muscle invasive bladder cancer.
Authors: Chen Xingyu , Qureshi Touseef , Xie Yibin , Knott Simon , Li Debiao , Rosser Charles Joel , Furuya Hideki 
Published: June 2023

e16587 Background: Accurate staging of Muscle Invasive Bladder Cancer (MIBC) is essential to ensure optimal treatment (e.g., radical cystectomy vs. bladder preservation). However, currently about 1/3 of patients are overstaged and 1/3 are understaged. There is a pressing need of accurate noninvasive staging for MIBC to assist clinical decision making. Methods: In this preliminary study, an extensive radiogenomic analysis of MIBC cases was performed to identify potential indicators of MIBC stages, and to automate the staging process. A total of 28 MRI scans and their matched transcriptomic profiles were obtained from subjects diagnosed with MIBC at different stages. In the genomics, a bulk RNA-seq from FFPE tissues was performed that identified 3 major clusters, high, intermediate, and low infiltrating immune cells and fibroblasts. This was followed by a bioinformatic analyses, such as pathway enrichment and gene set enrichment analyses, 15 most significant signatures were identified for stage categorization of MIBC (Fig. 1). In the radiomics, several hundred image-based features from bladder tumor in MRI were extracted and analyzed. The tumors were manually outlined and grouped into lower-stage (stage I and II) and higher-stage (stage III and IV) by the trained radiologists. Using various statistical tests, several radiomic features (e.g., heterogeneity, inverse contrast, entropy) were inferred as significant at discriminating the two groups (Fig. 2). A naïve Bayes machine learning model was then used to integrate such features and perform automated binary classification of cases into their true class. A 4-fold cross validation was performed in which a unique 75% and 25% of 28 cases were used for training and testing of the model respectively. Results: The model performance was assessed in terms of prediction (binary classification) of stages as mean sensitivity, specificity, and accuracy, reaching 84%, 86%, and 86% respectively. Conclusions: The radiogenomics of MIBC provides insight into features associated with cancer stages. Assisted with AI, the discriminative features can accurately stage MIBC. Source of Funding: Cedars-Sinai Cancer Internal Funds: Developmental Funds for Investigator Initiated Trials Using Advanced Imaging Methods.
UriFind assay and association with whole course management of urothelial carcinoma in a large multicentric, prospective China cohort.
Authors: Chen Xu , Liu Zheng , Zhou Liqun , Fan Jinhai , Ruan Weimei , Wang Hong , Wei Qiang , Chen Haige , Xu Tao , Li Lei , Wang Shaogang , Tan Wanlong , Xu Abai , Zhong Jianmei , Li Xia , Chen Zhiwei , Bibikova Marina , Fan Jian-Bing , Huang Jian , Lin Tianxin 
Published: June 2023

e16588 Background: The gold standard to diagnose and monitor urothelial carcinoma is cystoscopy, which is invasive and painful. The currently available non-invasive methods to detect urothelial carcinoma are either of unsatisfying sensitivity or limited specificity in China. Previously, a DNA methylation assay, termed UriFind, was developed, and showed a compelling sensitivity and specificity in a retrospective cohort. This study aimed to further validate its performance in a large multicentric, prospective China cohort. Methods: Patients involved in the whole course of UC management were recruited in this cohort. The cohort contained 931 patients diagnosed with urothelial carcinoma (UC), and 994 controls with benign diseases and 78 healthy participants from 12 hospitals across China. Urine samples were collected before the therapy, and analyzed with quantitative PCR of ONECUT2 and VIM methylation (UriFind), FISH and urinary cytology. Sensitivity, specificity, accuracy, PPV and NPV of these assays were evaluated as compared to the diagnostic gold standard of cystoscopy, histology results or clinical diagnosis. Results: The UC group of the cohort consisted of 683 non-muscle invasive UC (73.4%), 203 muscle invasive UC (21.8%) and 45 unavailable stage (4.8%). The patients of low, high-grade UC and unavailable grade were 244(26.2%), 651(69.9%) and 36 (3.9%), respectively. Overall sensitivity, specificity, accuracy, PPV and NPV of UriFind was 82.3%, 91.2%, 87.3%, 88.1% and 86.7%, respectively. The specificity of healthy participants was 100%. The overall sensitivity and accuracy of UriFind were significantly higher than urine cytology (40% and 55.7%) and FISH (68.2% and 73.6%), while the specificity was similar to cytology (93.9%) and FISH (87.3%). Importantly, UriFind achieved a great improvement of sensitivity in whole course management, including low grade tumor (56.1%), small and single tumor (63.3%), residual tumor after therapy (71.4%) and recurrent tumor (84.3%). Conclusions: The performance of UriFind is well validated with significantly higher sensitivity and accuracy than urine cytology and FISH in UC detection in this cohort with 2003 cases. This assay facilitates whole course management of urothelial carcinoma, which may reduce the burden of cystoscopy and unnecessary second TURBT. Clinical trial information: NCT04314245 .
Tislelizumab (Tisle) combined with/without gemcitabine and cisplatin (GC) as adjuvant therapy in patients at high risk after upper urothelial carcinoma (UTUC) surgery: A real-world study.
Authors: Yang Xiaojian , Quan Penghe , Yu Changjiang 
Published: June 2023

e16592 Background: In China, UTUC affects 9.3% - 19.9% of urothelial carcinoma(UC) patients(Pts), comparing to 5%-10% in western countries. Radical nephroureterectomy (RNU) is the standard of care for locally advanced UTUC; however, patient prognosis remains suboptimal, and previous studies have shown a controversial survival benefit of postoperative adjuvant chemotherapy in pts with UTUC. Immune checkpoint inhibitors(ICI) have been demonstrated to improve disease-free survival (DFS) in pts after adjuvant therapy for UC, but the data from UTUC studies is limited. This study is intended to evaluate real-world study data on whether Tisle with/without GC is able to achieve better survival benefit in pts with UTUC. Methods: UTUC pts with clinical diagnosis of T1N1 or T2-T4aN0-1M0, ECOG ps of 0-1, could tolerate surgery and had adequate renal functional reserve after surgery. Enrolled pts underwent RNU surgery and adjuvant therapy was started within 90 days after surgery. ICI: 200 mg in day1(D1), Q3w regimen, when to discontinue the drug was assessed by clinicians, and the reasons for disease progression and intolerable toxicity; GC chemotherapy: gemcitabine 1000 mg/m2 D1, D8, cisplatin 70 mg/m2 D2, up to 6 (0-6) cycles. Primary endpoint: 3-year Overall survival (OS) rate; secondary endpoints included 5-year OS rate, tumor-related survival (CSS) and safety. Results: A total of 60 pts received the above treatment from Jan 2020 to Dec 2022, of whom 5 pts were considered to have metastases at initial diagnosis at further evaluation and were finally evaluated for safety only. Fifty-five pts were evaluable for response, with a median follow-up time of 21.5 (3-33) months, and 70.91% (39/55) of pts were followed up for more than 12 months. The OS rate was 93.14% at 1 year and 76.21% at 2 years. Tisle was administered for a median of 6 (1-14) cycles, with a 7.19% and 24.79% lower risk of death at 1 and 2 years in pts with Tisle ≥ 3 cycles compared with pts with Tisle < 3 cycles (HR: 0.368, 95% CI (0.076-1.781); p = 0.162). GC was administered for a median of 3 (0-6) cycles, with a 3.7% and 24.8% lower risk of death at 1 and 2 years in pts with GC＞2 cycles compared with pts with GC≤2 cycles (HR: 0.218, 95% CI (0.045-0.970); p = 0.110). The incidence of treatment-related adverse reactions (trAEs) of any grade was 91.64%; the incidence of trAEs of grade 3-4 was 18.33%, mainly manifested as leukopenic, gastrointestinal reaction and thrombocytopenia. The incidence of immune-related adverse reactions (irAEs) was 25%, and no irAEs of grade 3 or higher were found. The enrollment and follow-up of the present study are currently ongoing. Conclusions: Encouraging efficacy data and safety have been preliminarily observed with adjuvant Tisle with/without GC chemotherapy in high-risk pts after UTUC surgery. Final results also need to be observed in further studies.
CarePoint assay in the management of bladder cancer: A pilot study.
Authors: Chang Sam S. , Linehan Jennifer , Scarpato Kristen R. , Bassett Jeffrey C. , Brenneman Rodney 
Published: June 2023

e16593 Background: Bladder cancer afflicts over 700,000 patients in the US and is one of the most expensive cancers to treat. Given a recurrence rate of up to 70%, regular often prolonged surveillance is required. In addition to urine based tests, current standard evaluation includes cystoscopy which is burdensome for patients and physicians; there has long been a need for a reliable non-invasive alternative diagnostic tool. While there is a wealth of literature on urinary biomarkers, no single biomarker has demonstrated consistent high sensitivity and specificity. Methods: The CarePoint Assay, a point-of-care (POC) tool, can perform multiple biomarker tests simultaneously. In this study, urine was collected from patients undergoing urologic evaluation for hematuria from three separate institutions. The urine was sent for central evaluation and the CarePoint Assay was used to detect the bladder cancer biomarker BTA. POC results were then compared to results from a highly sensitive 6-hour ELISA. The accuracy of distinguishing high-grade tumors, low-grade tumors and no tumor present were compared between the two methods. Results: The CarePoint Assay demonstrated excellent correlation with the ELISA in detecting biomarker levels and distinguishing high-grade tumors as well as a superior specificity (88% versus 77%) for ELISA, sensitivity (52% vs. 72%) for ELISA and a limit of detection of 2.55 ng/mL (16 picomolar). Conclusions: With this high performance, the CarePoint Assay has the ability to detect and multiplex multiple other bladder cancer biomarkers with higher sensitivity and specificity. Additional biomarker analysis using the CarePoint Assay may yield the medically desired higher levels of sensitivity and specificity for a non-invasive point-of-care bladder cancer test, ultimately limiting the patient burden of bladder cancer surveillance.
Performance of the OncoUrine test on the predictive capacity of non-muscle-invasive bladder cancer patients who are candidates for repeated transurethral resection.
Authors: Yang Xiao , Cai Lingkai , Liang Yiming , Xin Yaqun , Ma Tonghui , Lyu Qiang 
Published: June 2023

e16595 Background: According to European Association of Urology (EAU) guidelines, repeated transurethral resection of bladder tumor (re-TURBT) is recommended in a large percentage of high-risk non–muscle-invasive bladder cancers (NMIBC) due to possibility of incomplete initial TURBT. But so far, no diagnostic tests able to improve patients’ stratification exist to reduce negative biopsy ratio of re-TURBT. To evaluate the value of the OncoUrine test for the predictive capacity of biopsy findings on re-TURBT, a prospective multi-center clinical trial was designed. Methods: This was a blinded, observational, prospective multicenter study (NCT05112523). Between December 2020 and September 2022, patients with a confirmed diagnosis of high-risk NMIBC at three study centers were enrolled. The inclusion criteria were ≥age 22 years old, prepare for re-TURBT following EAU guidelines, able to produce 100 ml of morning urine, and able to consent. Urine samples were collected from the enrolled patients for the OncoUrine tests before re-TURBT, and the test results were compared with the pathological results to calculate the performance. High-throughput sequencing of 17 genes and methylation analysis for ONECUT2 CpG sites were combined as a liquid biopsy test panel named OncoUrine. Results: Out of 109 patients enrolled, 93 were eligible for the performance analysis. In 33 cases, residual tumors were confirmed while the remaining 60 patients was found to have a result of negative pathological section. In the overall OncoUrine test results, variants from 11 genes showed positive mutations. TERT C228T, TP53, TERT C250T, ERBB2 and PIK3CA were on the top 5 of the list with other mutations from FGFR3, KRAS, HRAS, ERBB3, ERCC2, U2AF1, and ROHA. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the OncoUrine test for predicting pathological diagnosis were 81.8% (27/33), 81.7% (49/60), 89.1% (49/55), and 71.1% (27/38), respectively. Conclusions: Even for high-risk patients for whom re-TURBT is currently recommended, the OncoUrine test can accurately differentiate between cases with incomplete primary surgeries and those with no residual tumors. An interventional clinical trial is needed to further confirm the clinical value of this urine-based biopsy method on improving the selections of NMIBC patients. Clinical trial information: NCT05112523 .
A novel approach to the treatment of high-risk non–muscle-invasive bladder cancer: Combining immune checkpoint inhibitor (ICI) and microtubule inhibitor (MTI).
Authors: Hu Hailong , Niu Yuanjie , Li Hong Zheng , Shen Chong , Huang Shiwang , Qie Yunkai , Wu Zhouliang , Zhao Gangjian , Zhang Zhe , Jia Kaipeng , An Zesheng , Chen Houyuan , Guo Shizheng , Bai Yiduo 
Published: June 2023

e16596 Background: Pts with multiple or tumors with large invasion areas that are incompletely resectable through TURBT would be recommended for radical cystectomy in the clinical treatment. The KEYNOTE-057 and SWOG S1605 studies have illuminated the efficacy of immune checkpoint inhibitors monotherapy in HR-NMIBC pts, with acceptable adverse events (AEs). This trial was designed to evaluate the efficacy and safety of tislelizumab (ICI) plus nab-paclitaxel (MTI) in HR-NMIBC pts. Methods: TRUCE-02 is a single-arm phase II study testing systemic tislelizumab 200mg on days 1 plus nab-paclitaxel 200mg on days 2 every 3 weeks (Q3W) for one year for NMIBC pts with incompletely resectable tumor by TURBT. Here we report the results for all eligible patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate when pts received 3 or 4 cycles of therapy. Duration of complete response (DOR), cystectomy-free survival (CFS), overall survival (OS), and progression-free survival (PFS) using Kaplan-Meier methods (KM) were secondary endpoints. Results: Between July 2020 and December 2022, 69 pts were enrolled and included in the safety analysis, and, of those, 56 pts were eligible and included in the efficacy analysis. 34 (60.7%; 95% CI 46.8%, 73.2%) out of 56 pts achieved CR condition when completing 3 or 4 treatment cycles. At 12 months, the estimated DOR after CR was 88.1% (95% CI 76.2%, 99.9%); the median DOR was not reached. At 18 months, the estimated CFS was 70.0% (95% CI 58.1%, 84.3%), OS was 90.6% (95% CI 82.9%, 99.0%), and PFS was 74.4% (95% CI 62.5%,80.0%); the median CFS, OS, and PRS were not reached. 65 (94%) of 69 pts had treatment-related adverse events (trAEs). The most common trAEs were alopecia 47(68%), fatigue 44(64%), and rash 25(36%). 8 grade 3-4 trAEs occurred in 6 (9%) pts, including adrenal insufficiency in 2 (3%), rash in 1 (1%), myalgia or arthralgia in 1 (1%), increased creatine kinase isoenzyme in 1 (1%), hepatic enzymes increase in 1 (1%), increased glutamyl transpeptidase in 1 (1%), and decreased white blood cell count in 1 (1%). No trAE-related death was reported. Conclusions: Tislelizumab with nab-paclitaxel represents a novel treatment option with a durable and clinically meaningful activity in treating HR-NMIBC. The safety profile was consistent with that of previous experience and no new safety concerns. Clinical trial information: NCT04730232 .
Clinical performance of Bladder EpiCheck methylation test for active surveillance of non-muscle invasive bladder cancer: Systematic review and meta-analysis.
Authors: HSIA YUANPING , Chiang Cho Hsien , Chiang Cho Han , Chiang Cho Hung , Wang Shih-Syuan , Chang Yu-Cheng , Jaroenlapnopparat Aunchalee , Shiah Her-Shyong 
Published: June 2023

e16597 Background: Non-muscle invasive bladder cancer (NMIBC) has a favorable 5-year survival, but up to 60% of patients experience cancer recurrence within the first year of diagnosis. The current gold standard for active surveillance is periodic cystoscopy, but this is expensive and invasive. An alternative non-invasive method involves urine cytology, but it has poor sensitivity. Recently developed urine-based molecular diagnostics such as the EpiCheck (Nucleix, Rehovot, Israel) test offers non-invasive and quick testing for active surveillance. In this systematic review and meta-analysis, we aimed to evaluate the diagnostic value of Bladder EpiCheck in active surveillance of NMIBC. Methods: We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies published between 1 January 2010 and 31 December 2022. The primary outcome was the sensitivity / negative predictive value (NPV) and specificity (PPV) of Bladder EpiCheck in active surveillance of NMIBC. We also performed a subgroup analysis to evaluate the performance of EpiCheck in detecting the recurrence of high-grade and low-grade NMIBC. Results: Our systematic search identified 110 articles, from which 6 studies were included in the final analysis. Compared with urine cytology, EpiCheck had a higher pooled sensitivity (73% [95% CI: 59-83] vs. 51% [95% CI: 30-72]) and NPV (90% [95% CI: 79.5-95.2] vs. 84% [95 % CI: 69-92]. However, EpiCheck had a lower pooled specificity (63% [95% CI: 48-76] vs. 97% [95% CI: 89-99]) and PPV (63% [95% CI: 48-76] vs. 85% [95 % CI: 69-94] than urine cytology. Similarly in subgroup analysis, EpiCheck had a higher pooled sensitivity than urine cytology in detecting both high-grade (86% [95% CI: 78-91] vs. 63% [95% CI: 43-80]) and low-grade (44% [95% CI: 34-55] vs. 13% [95% CI: 7-23]) NMIBC. Conclusions: The Bladder EpiCheck test has a better sensitivity than urine cytology and may be utilized as a part of the active surveillance strategy for NIMBC recurrence.