bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urine DNA model to predict response to neoadjuvant immune checkpoint inhibitors combined with chemotherapy in muscle-invasive bladder cancer.
Authors: Hu Hailong , Liu Huanhuan , Zhao Gangjian , Zhang Zhe , Shen Chong , Qin Jiayue , Cao Shanbo 
Published: June 2023

e16594 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise in the treatment of muscle-invasive bladder cancer (MIBC). However, not all patients benefit from the treatment. Urine can overcome shortcomings of tissue-based biomarkers to guide treatment decisions. Methods: Thirty-Three patients were recruited in this study and they received three cycles of tislelizumab 200 mg intravenously on day 1 plus nab-paclitaxel 200 mg intravenously on day 2 every three weeks, followed by surgical treatment. Acornmed 808 panel and shallow whole-genome sequencing were performed to predict the efficacy based on the urine DNA. Results: The urine ctDNA levels (highest variant allele fraction) were significantly lower in responder (CR and PR ) patients than this in non-responder (SD and PD) patients (p < 0.001). In addition, a decrease in chromosomal instability number (CIN) occurred in responding tumors (p = 0.028). Furthermore, ROC curves were used to compare the sensitivity and specificity of efficacy prediction, including the urine ctDNA level and CIN. In the ROC analysis, urine ctDNA level setting with an area under the ROC curve (AUROC) of 0.781 (95% CI 0.603 - 0.905, p = 0.005), achieving 100% sensitivity and 54.6% specificity in efficacy prediction. The ROC curve for CIN achieved a sensitivity of 68.2% and specificity of 72.7% (AUC = 0.731; 95% CI: 0.549-0.870, p = 0.013). Combination urine ctDNA level and CIN achieved a sensitivity of 100%, specificity of 63.6% (AUC = 0.806; 95% CI: 0.631-0.922, p = 0.002), positive predictive value (PPV) of 0.846, and negative predictive value (NPV) of 1.000. Conclusions: The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Cell-free urinary tumor DNA to detect minimal residual disease prior to repeat-transurethral resection of bladder tumor in non-muscle invasive bladder cancer: A prospective study.
Authors: Rose Kyle M. , Murthy Prithvi , Gould Billie , Huelster Heather L. , Davaro Facundo , Camperlengo Lucia P. , Du Pan , Jia Shidong , Vosoughi Aram , Grass G. Daniel , Spiess Philippe E. , Gilbert Scott Michael , Sexton Wade J. , Li Roger 
Published: June 2023

e16598 Background: Cell-free urinary tumor DNA (utDNA) generated from tumor genomic sequencing is an emerging biomarker showing tremendous potential for detecting minimal residual disease (MRD) in muscle-invasive and metastatic bladder cancer. We performed a prospective study to assess utDNA’s ability to measure MRD at the time of standard-of-care repeat transurethral resection of bladder tumor (rTURBT) in non-muscle invasive bladder cancer (NMIBC). Methods: Patients with high-risk NMIBC were enrolled prior to rTURBT. Index tumor and rTURBT mutational profile was performed via PredicineWES whole exome sequencing across 20,000 genes. Genes with non-synonymous (NS) mutations observed in index and rTURBT specimens identified in a minimum of two samples are reported. Urine samples were taken immediately prior to r-TURBT. utDNA detection was performed by ultra-deep sequencing of urinary cfDNA using a custom panel of up to 50-baseline mutations per patient together with a fixed core panel covering hotspot regions and actionable variants via PredicineBEACON Urinary tumor fraction was used to call utDNA positivity. The primary endpoint was the detection of utDNA to predict MRD at the time of repeat-TURBT. Results: Eleven patients underwent rTURBT for high risk NMIBC. Residual tumor was detected at rTURBT in 8/11 (73%) patients. Fifty genes with NS mutations found in at least two samples were identified including TP53, PIK3CA, RB1, MYC, CDKN1A and ARID1A. A median of 146 (range 39-418) and 91 NS (range 2-312) mutations were identified in the index and re-TUR specimens, respectively. Concordance rates were 83% on average between primary and rTURBT, highest for patients upstaged to T2 disease, and lowest for patients harboring CIS. Genomic alterations in urinary tumor DNA were detected in ten patients. The tumor fraction of utDNA was higher in patients with residual disease (mean 2.5% vs. 0.2%, p=0.10). Using tumor-fraction to predict MRD, the area under the receiver-operator curve (AUC) for this test was 0.85. Using an optimal threshold of ≥3.3% tumor-fraction to define utDNA positivity, the test had a sensitivity of 75% at 100% specificity. Conclusions: Urinary tumor DNA shows promise as a surrogate for minimal residual disease and may predict TURBT pathology for NMIBC. Genomic alterations between index and rTURBT tumors are highly concordant in papillary tumors even in the setting of upstaging, which may aid in targeted intravesical or systemic therapy selection. Larger cohorts and long-term follow up is needed to determine if utDNA can risk-stratify patients prior to rTURBT and predict long-term recurrence.
Tislelizumab in combination with gemcitabine plus cisplatin as neoadjuvant therapy for lymph node‐positive bladder cancer.
Authors: Yang Xiao , Cao Qiang , Li Pengchao , Cai Lingkai , Zhuang Juntao , Lyu Qiang 
Published: June 2023

e16599 Background: Although multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs combined with gemcitabine plus cisplatin in MIBC, lymph node‐positive bladder cancer is generally excluded. Our specific aim was to compare the efficacy and prognosis of neoadjuvant tislelizumab combined with gemcitabine plus cisplatin in patients with lymph node‐positive bladder cancer. Methods: In this single arm phase II study, eligible patients had cT2-T4a N+ M0 MIBC, cisplatin-eligible, and to be planned radical cystectomy (RC). Patients received tislelizumab 200 mg in day D8, cisplatin 70 mg/m2 D2, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for 3 or 4 cycles. RC was performed within 6 weeks after last dose treatment. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging ( < ypT2), EFS, OS and safety. Results: By Jan 2023, 17 eligible pts (2cT2, 10 cT3, 5 cT4) were enrolled. 14 pts have completed neoadjuvant therapy, with median age of 67 (60-81) years, among whom 10 pts underwent RC and two declined RC. According to RECIST 1.1, 6 pts achieved a clinical complete response (cCR)(6/14,42.8%). Pathological results revealed 5 pCR (ypT0N0, 50%), 3 ypT1N0, and 2 ypT2/T3N0. A complete nodal response (pN0) occurred in 10 (100%) pts post- tislelizumab +chemotherapy and 8 ( < ypT2N0,80%) pts achieved pathologic downstaging. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (11/14,78.5%), nausea (9/14,64.2%), vomiting (8/14,57.1%), decreased appetite (6/14,42.8%), fatigue (4/14,28.5%), pruritus (3/14,21.4%) and ALT/AST increased (4/14,28.5%). Grade ≥3 neoadjuvant therapy related AEs were neutropenia (n = 3), thrombocytopenia (n = 2), anemia (n = 2). One patient discontinued GC plus tislelizumab due to AEs. Conclusions: Patients with clinically lymph node‐positive bladder cancer have significant pN0 after neoadjuvant therapy. Neoadjuvant tislelizumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in lymph node‐positive bladder cancer. Clinical trial information: NCT04570410 .
ANTICIPATE phase I: Oral APL-1202 in combination with tislelizumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC).
Authors: Galsky Matt D. , Sfakianos John P. , Ye Ding-Wei , Song Xiaodong , Hu Hailong , Shore Neal D. , Zhang Xiaoping , Zhang Mingming 
Published: June 2023

e16607 Background: APL-1202 (nitroxoline) is a reversible and orally available MetAP2 inhibitor with anti-angiogenic and anti-tumor activities. Single-agent neoadjuvant programmed death 1 (PD-1) antibodies achieve pathological complete responses in a subset of patients with MIBC. APL-1202 and PD-1 antibody combination therapy demonstrates synergistic effects in several model systems of cancer, including bladder cancer. We hypothesized that APL-1202, in combination with tislelizumab, a humanized IgG4 anti-PD-1 antibody, may be an effective neoadjuvant therapy in MIBC. Methods: ANTICIPATE Phase I was a dose escalation study to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of APL-1202. Eligible patients had newly diagnosed MIBC, were cisplatin-ineligible or refused cisplatin-based neoadjuvant chemotherapy, and were planned for radical cystectomy (RC). A standard 3+3 dose-escalation design was employed. On day 1 of each cycle, a single dose of 200 mg tislelizumab was administered intravenously. APL-1202 was administered orally 3 times daily and with the dose escalated in 3 successive cohorts (375 mg, 750 mg, and 1,125 mg). Intra-patient dose escalation was not allowed. Blood samples were collected for pharmacokinetics and other translational studies. Results: Nine patients have been enrolled in phase I: 3 patients each at 375 mg, 750 mg, and 1125 mg of APL-1202. All patients had predominant urothelial cancer with cT2 (6/9) and cT3 (3/9); PD-L1 expression was assessed using the VENTANA PD-L1 (SP263) Assay and 1/9 (11.1%) patients was positive. No dose-limiting toxicities were observed at either 375 mg, 750 mg, or 1125 mg daily dose of APL-1202. Treatment-related adverse events (TRAE) were observed in 6 patients. All AEs were grade 1, except 1 grade 2 T wave abnormality on ECG and 1 grade 3 liver dysfunction. No grade 4 or 5 related AEs were observed. The patient with grade 3 liver dysfunction recovered to baseline within 2 weeks and underwent RC. Pathologic downstaging to < pT2 was observed in 5/8 (62.5%) and 1/8 (12.5%) with pT0 in 8 evaluable patients; 1 patient refused RC. Conclusions: APL-1202 plus tislelizumab was well tolerated. The RP2D of APL-1202 was identified as 1125 mg daily dose. Early efficacy signals were observed including pathologic downstaging to < pT2 (5/8, 62.5%) and pT0 (1/8, 12.5%). Phase 2 trial was ongoing. (NCT04813107). Clinical trial information: NCT04813107 .
Preoperative oral antibiotic bowel preparation regimens in radical cystectomies with continent diversion.
Authors: Simhal Rishabh , Wang Kerith Ruoyao , Poluch Maria L. , Shah Yash , Leong Joon Yau , Shah Mihir S. , Gomella Leonard G. , Chandrasekar Thenappan , Lallas Costas D. 
Published: June 2023

e16610 Background: Bowel preparation regimens (BRs) were historically standard before radical cystectomy (RC) with urinary diversion to decrease infection and anastomotic breakdown. However, the Enhanced Recovery After Surgery protocol (ERAS) no longer includes BRs. Recent data show that BRs may exacerbate frailty, worsen surgical outcomes, and prolong recovery. Importantly, however, previous studies did not stratify by diversion type. We performed a population-based analysis of preoperative oral antibiotic BRs (OABRs) with RC, alongside subgroup analyses to compare outcomes by diversion type. Methods: RCs performed from 2019-2020 were identified using the new NSQIP Cystectomy-Targeted PUF. Captured variables included OABR, diversion type, demographics, comorbidities, and perioperative outcomes. Univariate analysis with two tailed chi square and t tests was performed to compare baseline characteristics, 30-day mortality, and complications. Multivariable logistic regression with stepwise-backward-elimination (p > 0.25) adjusted for mechanical BRs, operative approach, comorbidities, functional status, demographics, ASA class, labs, and staging. Results: In total, 3,894 RCs were performed, of which 357 (9.2%) included OABR. There were no significant baseline differences between the OABR and the non-OABR cohorts. On univariate analysis, OABR patients had increased operative time, length of stay (LOS), minor complications, and bleeds. On subgroup analysis, ileal conduit patients experienced higher rates of the 4 aforementioned outcomes plus deep wound infections and NGT use. However, the continent diversion subgroup was not associated with increased operative time, LOS, or any complications. Continent diversion had significantly lower rates of sepsis and ureteral fistula formation. Upon multivariable adjustment, OABR was not associated with increased rates of any complications across any subgroup. OABR did confer significantly decreased odds of sepsis in continent diversion patients. Conclusions: Supporting ERAS recommendations, this study showed that pre-RC OABRs do not improve outcomes and increase LOS for ileal conduits. However, this study uniquely included continent diversions, such as neobladders and Indiana pouches. Importantly, in continent diversion patients, OABR did not increase LOS or complications while decreasing sepsis rates. These findings suggest possible utility of OABR before RC with continent diversion.
Clinical efficacy analysis of patients (pts) with HER-2 expressing metastatic urothelial carcinoma (mUC) treated with enfortumab vedotin (EV).
Authors: Jiang Cindy , Alhalabi Omar , Haro-Silerio Jaime , Qiao Wei , Shah Amishi Yogesh , Siefker-Radtke Arlene O. , Gao Jianjun , Goswami Sangeeta , Alva Ajjai Shivaram , Koshkin Vadim S. , Guo Charles , Campbell Matthew T. 
Published: June 2023

e16618 Background: EV, an antibody drug conjugate (ADC) targeting NECTIN-4, is an approved salvage treatment for unselected pts with mUC. ADCs targeting the human epidermal growth factor receptor-2 (HER-2) have also shown robust activity in clinical trials for mUC with tumor HER-2 expression. We investigated the interaction between HER-2 expression and clinical outcomes of pts treated with EV, which are currently unknown. Methods: We conducted a retrospective, single institution study analyzing pts with mUC who received EV. Immunohistochemistry (IHC) staining for HER-2 was completed with PATHWAY anti-HER2 (4B5) Antibody (Ventana Medical Systems, Tucson, AZ) using established breast cancer scoring algorithm. Wilcoxon rank sum and Fisher exact tests were used to compare continuous and categorical variables, respectively. Cox proportional hazards regression model was used to evaluate a variable’s ability to predict overall survival (OS). Variables with p-value ≤0.1 were included in the multivariate analysis (MVA). Results: We identified 158 pts with mUC who received EV. Median age at EV start was 70 (IQR 66-76), most pts were Caucasian (144, 91%), male (108, 68%), primary bladder tumors (113, 72%), and pure urothelial histology (95, 60%). 96 pts (61%) received prior platinum therapy and 117 pts (74%) had prior immunotherapy. ECOG scores ≥2 was seen in 54 pts (39%) while 75 pts (54%) had Bellmunt scores ≥2 (54%). Median follow up time was 12.5 months and median OS from EV start was 13 months. 94 pts (60%) had HER2 IHC staining. There was no association between HER2 intensity and any of the clinical variables. On univariate analysis (UVA): HER2 3 vs HER2 ≤2 HR was 0.38 (0.14, 0.98), male vs female HR=1.56 (0.94, 2.58), ECOG ≤1 vs ≥2 HR=0.6 (0.38,0.95), Bellmunt score 0-1 vs 2-3 HR=0.49 (0.3, 0.78), and hemoglobin (Hgb) HR=0.75 (0.67, 0.85). MVA showed HER2 3 vs HER2 ≤2 HR was 0.42 (0.16, 1.12), male vs female HR=2.3 (1.17, 4.42), ECOG ≤1 vs ≥2 HR=0.56 (0.30, 1.05), and Hgb HR=0.77 (0.65, 0.92). Conclusions: MVA of this single-site retrospective cohort did not show any association between HER2 expression and survival outcomes in pts with mUC who received EV. Further studies are needed to continue assessing the role of HER2 as a potential prognostic and predictive biomarker in UC, especially if HER-2 directed therapies become incorporated in the mUC treatment paradigm. [Table: see text]
Preclinical development of RAG1-40-31L: A novel small activating RNA-lipid conjugate targeting tumor suppressor gene p21 for treatment of non-muscle invasive bladder cancer.
Authors: Jarvelainen Harri , Lin Wei-Hsiang , Kang Moorim , Zhou Xiaojie , Place Robert F. , Li Long-Cheng 
Published: June 2023

e16620 Background: Loss-of-function of tumor suppressor genes are the dominant driving force in tumorigenesis. Restoration in function and/or expression of these genes holds tremendous therapeutic potential in cancer treatment. Bladder cancer is the 9th leading cause of cancer-related deaths in the United States in which ~75% of all newly diagnosed cases are non-muscle invasive bladder cancer (NMIBC). Standard-of-care includes intravesical installation of Bacillus Calmette-Guerin following tumor resection with an expected failure rate of ~50% within 6 months for patients with high-grade tumors. RNA activation (RNAa) is a mechanism in which short RNA duplexes termed small activating RNA (saRNA) induce gene transcription by targeting non-coding regulatory sequence ( i.e., promoters) embedded in chromatin. Thus, saRNA-induced overexpression of p21WAF1/CIP1 (p21) – a tumor suppressor of several anti-growth pathways – may hold therapeutic potential in bladder cancer. Through conjugation of a novel lipid ( i.e., C5X5), we have created a p21-targeting saRNA drug candidate referred to as RAG01-40-31L for delivery to bladder cancer cells in vivo. The aim of this work was to characterize the intravesical administration of RAG01-40-31L on p21 induction and its anti-tumor potential in NMBIC models. Methods: In vitro expression analyses were performed to investigate p21 induction via saRNA in KU7 and T24 bladder cancer cell lines by RT-qPCR and immunoblot analysis. Cell cycle analysis and tumorigenicity assays examined impact of RAG1-40-31L on cancer cell growth. Orthotopic human bladder tumors were established in female BALB/c nude mice using the recombinant cell line KU7 engineered to overexpress luciferase reporter. Tumor growth was monitored in live animals via luciferase bioluminescence using an in vivo imaging system. Plasma and tissue were harvested for drug exposure and expression analytics. Results: In vitro analyses indicated RAG1-40-31L activated p21 expression by approximately 6-fold and inhibited bladder cancer cell growth ( i.e., cell cycle arrest, apoptosis, and senescence) in a dose-dependent manner with low nanomolar potency. Intravesical administration of RAG1-40-31L (3 times per week for 2 weeks) inhibited growth of orthotopic tumors by 65% in mouse bladder models. Single-dose pharmacokinetics demonstrated a half-life (t1/2) of ~114 h with minimal systemic exposure (~0.05% of that of bladder tissue). Conclusions: These data constitute a preclinical proof-of-concept for saRNA as a novel p21-targeting modality in the treatment of cancer. The C5X5 lipid conjugate appears to be a viable approach to enhance oligonucleotide delivery and activity in bladder cancer. Preclinical safety assessment studies to enable clinical trials of RAG01-40-31L are currently underway.
Baseline endogenous serum testosterone levels and all-cause mortality in men with prostate cancer treated by radical radiotherapy: 11-year follow-up data.
Authors: Sundar Santhanam , Shawcroft Ewan , Jones Lauren , O'Cathail Micheal , Hosni Shaymaa Usama , Little Jessica , Walker Georgina , Cox Ashley , Fergusson Eamonn 
Published: June 2023

e17003 Background: Low levels of serum testosterone are associated with higher all-cause mortality and cardiovascular mortality in some studies.(PMID: 18040028). But men with low levels of serum testosterone at reduced risk of developing prostate cancer. (PMID: 30077399). In middle-aged and elderly men, single point testosterone measurements have been shown to reliably reflect long term androgen exposure. [PMID: 1548361]. We assessed the interaction of pre-treatment serum testosterone levels and long term all-cause mortality in men with newly diagnosed prostate cancer. Methods: Prostate cancer pts enrolled in an ethics approved, prospective study evaluating a rating scale. Baseline serum testosterone levels were measured before the pts were commenced on androgen deprivation therapy and radical radiotherapy. Patient characteristics: Mean age 68.2yrs (median 69yrs); Age range category < 60yrs:14.9% , 61-70yrs:47.3% and > 71 yrs: 37.8%. Charlson Comorbidity Index (CCI) prevalence at baseline as follows CCI- Low risk : 39.9%; CCI-medium risk : 51.4%; CCI-high risk: 8.8%. PSA median level was 10.85 ug/L. Tumour was localised in a majority of pts- stage T1/T2 in 72% . Pts with M1 disease were not enrolled. Histology grade: Gleeson grade 6 in 7.4% and Gleeson grade 7 in 53.4% . Serum testosterone: Median 11.9 nmol/l; Mean 12.4 (Min-Max 2.6 to 26.7). Cox proportional hazards regression used to analyze the effect of baseline Serum Testosterone on long term overall survival, while controlling for covariates (age, cancer T stage, PSA category, Gleeson Category and Charlson Comorbidity index). Results: Lower levels of serum testosterone at baseline were associated with decreased all-cause mortality. There was no significant correlation between testosterone levels and age in our study sample of relatively elderly population (Pearson Correlation p = 0.362); There was no correlation testosterone levels and PSA levels(P = 0.821); no association between serum Testosterone levels and Gleeson Grade as well as T stage. (F = 0.78 ; P = 0.46 and F = 1.34 ; P = 0.26 respectively). There was also no significant variation in testosterone levels according to Comorbidity categorised by Charlson Comorbidity Index. (F = 1.31 P = 0 .26). Conclusions: Lower Serum testosterone levels were associated with decreased all-cause mortality in this prospectively collected survival data of non-metastatic Prostate cancer patients. [Table: see text]