bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between CD47 expression and clinicopathologic characteristics and survival outcomes in MIBC.
Authors: Myint Zin , Jayswal Rani , Chahine Zena , Bachert Sara E , McDonald Robert J , Allison Derek B. 
Published: February 2022

534 Background: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for these. CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) on transurethral resection of bladder tumor (TURBT) who subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by immunohistochemistry in both TURBT and matched RC specimens. Expression levels ≥1% were considered positive. The difference between CD47 expression levels between TURBT and RC were also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes were evaluated by Person’s chi-squared test and Kaplan-Meier method respectively. Results: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. The majority of patients were Caucasian (95%), male (79%), and age > 60 (63%). Most patients (75%) underwent NAC prior to RC. Of those who received NAC, 35% were responders and 64% were non-responders. Responders includes those with a pathologic complete response (T0) or partial response (Tis or T1); non-responders included those with stage ≥ T2. The final reported stages for all patients were as follows: stage 0 (32%), stage I (1%), stage II (20%), stage III (43%), and stage IVA (5%). 60% of patients were alive, 40% died from bladder cancer, and 30% had disease recurrence at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients > 60 (p = 0.006), non-responders (p = 0.002), stage ≥ III (p < 0.001) were associated with worse OS by univariate analysis. There was no significance with multivariate analysis. There was a slight positive trend for decreased CD47 levels between TURBT and RC in patients who received NAC (p = 0.5), though this did not reach statistical significance. Conclusions: CD47 expression is not a prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore a potential role for anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend between decreased CD47 levels (from TURBT to RC) in patients receiving NAC. More research is needed to understand how NAC may or may not modify immune surveillance mechanisms in MIBC.
SWOG S1314: A randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer with overall survival follow up.
Authors: Flaig Thomas W. , Tangen Catherine , Daneshmand Siamak , Alva Ajjai Shivaram , Lucia M. Scott , McConkey David , Theodorescu Dan , Goldkorn Amir , Milowsky Matthew I. , Bangs Rick , MacVicar Gary R. , Bastos Bruno R. , Fowles Jared , Gustafson Daniel , Plets Melissa , Thompson Ian Murchie , Lerner Seth P. 
Published: February 2022

536 Background: This trial evaluated COXEN, a gene expression model, as a predictive biomarker in muscle-invasive bladder cancer (BC) patients randomized to Gemcitabine-Cisplatin (GC) or dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC). Primary results correlating COXEN with pathologic response at surgery have been reported. This secondary analysis includes progression-free (PFS) and overall survival (OS). Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. Cox regression was used to evaluate COXEN score or treatment arm association with PFS and OS, adjusting for stratification factors (stage and PS). Results: 167 patients were included in the primary COXEN analysis all having either at least 3 cycles of chemo and surgery within 100 days of last chemo or having progressed while receiving chemo. The COXEN scores were not significantly prognostic for OS or PFS in their respective arms; the COXEN GC score was a significant predictor for OS in pooled arms. OS and PFS data are shown for both scores in the table. In the intent to treat analysis (n=227), there was no significant difference in OS or PFS for ddMVAC versus GC (for OS, HR =0.87, 95% CI 0.54-1.40), p = 0.57); for PFS (HR= 0.76 95% CI 0.58-1.01, p = 0.055). Association of path response with OS will be presented. Conclusions: The COXEN GC score may be prognostic of survival in those receiving platinum-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and PFS for GC and ddMVAC that appear comparable, but this phase II trial is underpowered for definitive comparisons. The prospective data and correlative samples from S1314 will allow for further assessment of COXEN and other RNA and DNA based predictive and prognostic biomarkers. Clinical trial information: NCT02177695. [Table: see text]
Novel use of ctDNA to identify locally advanced and metastatic upper tract urothelial carcinoma.
Authors: Huelster Heather L. , Green Elizabeth A. , Soupir Alex C. , Katende Esther N. , Rose Kyle M. , Naidu Shreyas U. , Gilbert Scott Michael , Manley Brandon J. , Poch Michael Adam , Sexton Wade J. , Spiess Philippe E. , Yu Alice , Kim Youngchul , Du Pan , Jia Shidong , Kim Il-Jin , Tan Lu , Wang Liang , Li Roger 
Published: February 2022

543 Background: Upper tract urothelial carcinoma (UTUC) is an aggressive cancer for which use of neoadjuvant chemotherapy (NAC) is limited by suboptimal clinical staging prior to nephroureterectomy. Detection of circulating tumor DNA (ctDNA) is associated with locally advanced and metastatic urothelial carcinoma of the bladder and may help identify UTUC patients who would benefit from NAC. Here we examine the feasibility and utility of plasma ctDNA in the diagnosis of non-organ confined high-risk UTUC. Methods: Patients with high-grade cTa-T2 UTUC without radiographic evidence of metastatic disease undergoing up-front radical nephroureterectomy (RNU) were prospectively accrued. Blood was collected preoperatively on the day of surgery, and plasma and buffy coat were processed for extraction of ctDNA. FFPE samples from RNU were used for tissue genomic DNA extraction. Next-generation sequencing (NGS) was used for variant profiling. Plasma and somatic tissue mutations were called by comparing with matched buffy coat samples. Detection of cancer variants with a mutation allele frequency (MAF) ≥ 0.25% and hotspot variants with a MAF down to 0.1% were reported for plasma samples targeted by a NGS panel (PredicineCARE). Variants with a MAF ≥ 5% and hotspot variants with a MAF down to 2% were reported for FFPE samples. Results: NGS analyses of matched FFPE and plasma samples were successfully performed for all 15 accrued UTUC patients. Alterations in MYC amplification (62%), TERT promoter (62%), TP53 (38%), FGFR3 (31%), ERBB2 (25%), ARID1A (19%), and PIK3CA (19%) were demonstrated in urothelial tumor tissue. Matched plasma ctDNA showed prevalent alterations in the TERT promoter (47%), TP53 (30%), ARID1A (20%), ERBB2 (20%), FGFR3 (20%), and PIK3CA (17%). Five patients (33%) had detectable plasma ctDNA mutations concordant with tumor-based genotypes using the targeted NGS panel. All patients with detectable preoperative ctDNA had advanced staging (≥pT2 or ≥pN1) and lymphovascular invasion on final pathology, resulting in a 71.4% sensitivity. The panel was 100% specific with no patients with pTis, pTa, or pT1 and pN0 having detectable concordant ctDNA mutations. Conclusions: Prospective ctDNA analysis using a targeted NGS panel is a feasible nonsurgical approach to prediction of high-risk UTUC and has the potential for identification of upper tract urothelial cancer patients that may benefit from NAC.
Prognostic impact of serum cytokeratin 19 fragments in patient with metastatic urothelial cancer treated with immune checkpoint inihibitors.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Takeda Hayato , Yanagi Masato , Mikami Hikaru , Ikuma Shunsuke , Toyama Yuka , Kondo Yukihiro 
Published: February 2022

555 Background: Recent clinical trials such as Keynote-045, EV-201 and Javelin bladder100 have provided new therapeutic agents for metastatic urothelial carcinoma (mUC). However, the only tool that can evaluate the therapeutic responses is a radiological criteria, Response Evaluation Criteria in Solid Tumors (RECIST) in mUC. In the clinical practice, biomarkers that can predict the efficacy and prognosis of various agents are essential to treat these patients, and the search for such biomarkers is urgently needed. We reported that Performance status ≥ 1, liver metastasis and elevated serum cytokeratin 19 fragments (sCYFRA) are the prognostic factors for first-line cytotoxic cheomotherapy (CTC) for mUC. In this study we evaluated pretreated clinical biomarkers including sCYFRA that can predict overall survival (OS) in patients with mUC treated with immune-checkpoint inhibitors (ICI). Methods: Thirty four patients with mUC received pembrolizuab (PB) from February 2018 to July 2020 at our institution. We retrospectively collected performance status, metastasis site, blood neutrophil-lymphocyte ratio (NLR), hemoglobin (Hb), and serum levels of lactose dehydrogenase (LD), alkaline phosphatase (ALP), C-reacted protein (CRP), total protein, albumin, corrected calcium (Ca), carbohydrate antigen19-9, sCYFRA before PB was administered. OS rate were analyzed by Kaplan-Meier curves and log-rank test. Multivariate analysis was carried out using the Cox hazards model. Objective Response rate (ORR) was evaluated based on RECIST (version 1.1). Results: Of 34 patients (Pts), with median age of 73(31-86), during the median follow-up period of 25 (7-126) months, 21patients (65%) had died. Median OS was 9.2 months (0.2-33.4), A 1-year OS rate was 33%. ORR was 33% and 9 Pts was SD (27%) and 14 pts (40%) was progressive disease. On univariate analysis, bone metastasis (p=0.028), LD (p=0.003), ALP (p=0.001), Ca (p=0.003) and sCYFRA (p=0.001) were the significant prognostic factor for OS. On multivariate analysis, ALP (HR9.2, 95%CI [2.89-135.9], p=0.002), Ca (HR7.3, (95%CI [2.36-22.49], p=0.001), sCYFRA (HR 5.0, 95%CI [1.63-15.55], p=0.005) were the significant prognostic factor for OS. Based on these 3 factors we divided pts into three groups, good risk (G1,0 factor), intermediate risk (G2, 1 factor) and poor risk (G3, 2-3 factors)3. There was a significant difference between the three groups for OS on K-M curve (G1 vs G2, p=0.001, G2vs G3, p=0.009). Conclusions: sCYFRA, ALP and Ca were the independent prognostic factors for OS in patients with mUC treated with ICI. sCYFRA was the independent prognostic factor for OS in the 1st line CTC and 2nd line ICI and it can be a prognostic factor though those therapies.
Prognostic value of HER2 expression levels for upper tract urothelial carcinoma.
Authors: Li Siming , Wu Xiaowen , Yan Xieqiao , Zhou Li , Xu Huayan , Li Juan , Liu Yiqiang , Tang Bixia , Chi Zhihong , Si Lu , Guo Jun , Sheng Xinan 
Published: February 2022

557 Background: HER2 expression is an adverse prognostic factor of bladder urothelial carcinoma (UBC) while the prognostic value of HER2 expression in upper tract urothelial carcinoma (UTUC) remains to be explored. This study aims to investigate the prognostic value of different HER2 expression and gene amplification levels in UTUC. Methods: The baseline clinicopathological data of 130 patients with UTUC were reviewed. The expression level of HER2 was detected by immunohistochemistry (IHC) staining ( Anti-Her2/neu, Cat.4B5, Ventana ) from formalin-fixed paraffin-embedded (FFPE) tumor tissue of patients. The HER2 gene amplification level was detected by second-generation sequencing (NGS) (HER2 gene copy number [CN]) or Fluorescence in situ hybridization (FISH) from FFPE tumor tissue of patients. HER2 negative was defined as IHC 0. HER2 low expression was defined as IHC 2+ but CN- or FISH-, while HER2 overexpression included IHC 3+, and IHC 2+ but CN+ or FISH+. The correlation between HER2 expression levels or other clinicopathological characteristics and overall survival (OS) were analyzed. The Cox proportional-hazards model was used to analyze the independent prognostic factors of UTUC. Results: All the 130 patients provided FFPE tumor slides for the IHC detection of the HER2 expression levels including: IHC 0 (n = 47), IHC 1+ (n = 28), IHC 2+ (n = 41) and IHC 3+ (n = 14), the median OS were 27.5 months, 48.7 months, 67.3 months, and not reached, respectively, with significantly difference ( P = 0.014). Among the 41 patients with HER2 IHC 2+, 15 patients received the detection of the HER2 gene amplification level by NGS or FISH while the other 26 patients whose HER2 gene amplification levels were unknown were excluded from the analysis. The patients of HER2 negative, low expression, and overexpression had a median OS of 27.5 months, 58.0 months, and 60.0 months, respectively, but the difference was not significant ( P = 0.184). Cox proportional-hazards model also verified that the HER2 IHC expression is an independent prognostic factor on the survival, while the prognostic value of the HER2 gene amplification levels was not found. Conclusions: HER2 IHC expression is an independent factor for the prognosis of patients with UTUC. However, HER2 gene amplification levels have no impact on the prognosis of UTUC patients. HER2 expression especially the HER2 gene amplification level in UTUC needs to be explored further.
Association between TERT promoter mutations and clinical outcome with immune checkpoint inhibitor therapy for advanced urothelial cancer.
Authors: Chawla Neal Shiv , Tripathi Nishita , Sayegh Nicolas , Govindarajan Ameish , Dizman Nazli , Zengin Zeynep Busra , Meza Luis A , Muddasani Ramya , Chehrazi-Raffle Alex , Salgia Sabrina , Malhotra Jasnoor , Hsu Joann , Philip Errol James , Bergerot Cristiane Decat , Lyou Yung , Swami Umang , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Pal Sumanta K. 
Published: February 2022

561 Background: Recently published data suggests that the presence of a TERT promoter mutation is predictive of superior overall survival (OS) in patients (pts) with advanced/metastatic bladder cancer (mUC) treated with an immune checkpoint inhibitor (ICI) (Kouchkovsky et al, JITC 2021). We aim to validate the results of this study in a large independent cohort. Methods: Pts with mUC treated at two tertiary cancer centers with available genomic data collected in the course of routine clinical care were identified retrospectively. Pts that had received at least one line of ICI therapy in the metastatic setting were selected. Demographic and treatment data were collected, with pts divided into two groups based on the presence or absence of TERT mutation status ( TERTm or TERTwt, respectively). We evaluated OS from diagnosis of at least muscle invasive disease, progression free survival (PFS), and objective response rate (ORR) with ICI therapy across the two groups. OS in our cohort was compared with findings from pts with bladder cancer in The Cancer Genome Atlas (TCGA) database. Results: From our combined data sets, a total of 166 pts had available genomic data, with 64 TERTm pts (52:12 M:F) and 58 TERTwt pts (32:26 M:F) meeting criteria for inclusion. Median age at diagnosis was 67 in both groups. The site of primary disease was bladder in 54 (84%) TERTm vs. 41 (71%) in TERTwt; 10 (16%) and 17 (29%) had upper tract disease, respectively. 47 (73%) TERTm pts and 40 (69%) TERTwt pts had pure urothelial disease; 17 (27%) and 18 (31%) pts had mixed/pure variant histology, respectively. 37 (58%) and 42 (72%) pts received first-line ICI therapy whereas 27 (42%) and 16 (28%) received subsequent-line therapy in TERTm and TERTwt, respectively. At the time of analysis, there were 24 (38%) patients alive in TERTm, and 23 (40%) patients alive in TERTwt. OS was 35 vs. 36 mos (95% CI 0.62-1.51, P=0.66) in TERTm and TERTwt, respectively. PFS on ICI therapy was 4.6 vs. 5.3 mos (95% CI 0.58-1.34, P≥0.99) in TERTm and TERTwt, respectively. ORR was 75% in TERTm and 50% in TERTwt (P=.004). OS in the TCGA database was 35 mos in TERTm and 47 in TERTwt (P=0.19) from a total of 311 and 127 pts, respectively. Conclusions: In contrast to previously published data, our data show no difference in OS and PFS on the basis of TERT mutational status in pts with mUC treated with ICI therapy. Further analysis from larger datasets is needed to reconcile the role of TERT mutations within this patient population.
Genomic characterization and identification of actionable variants in patients with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Stecca Carlos , Selvarajah Shamini , Jiang Di Maria , Abdeljalil Osama , Zhang Tong , Bedard Philippe L. , Hansen Aaron Richard , Fallah-Rad Nazanin , Sridhar Srikala S. 
Published: February 2022

562 Background: Next generation sequencing (NGS)-based molecular profiling has been widely used across various tumor types including genitourinary malignancies to better understand and potentially predict tumor behavior. The goal of this study was to determine the feasibility of using NGS to characterize mUC and to identify potentially actionable variants. Methods: Patients with locally advanced or metastatic urothelial carcinoma (mUC) treated at the Princess Margaret Cancer Center were prospectively recruited for the OCTANE study, which collects archival tumor samples to provide genomic characterization through NGS with a custom hybridization capture DNA-based panel (555 genes) or a targeted DNA/RNA amplicon panel (Oncomine Comprehensive Assay v3, 161 driver gene panel). Variants were annotated using a somatic variant scheme [PMID: 25880439] or the oncoKB database. Comprehensive clinical information including patient, disease and treatment characteristics was collected using electronic patient records. Kaplan-Meier and cox regression were used for survival analysis. Results: Of the 73 patients, median age was 65 (23-83), majority were men (69%), most had lower tract disease (80%) and 41% had de novo metastatic disease. NGS was deemed feasible, based on availability of tumor samples, and performed in 67 (92%) patients. Overall, 61 (91%) had at least one oncogenic variant, including 34 (56%) with a potentially "druggable" target. The most frequent genomic alterations found were TP53 (44%), FGFR (18%), TERT (18%), ARID1A (18%) and PIK3CA (16%), all classified as "pathogenic/likely pathogenic". Only 2 patients received targeted treatment, one as part of clinical trial and one as standard of care. mOS was numerically longer among patients with genomic mutations compared to the ones without: 55 vs 31 months (HR: 0.87, CI 95% 0.3-2.4; p:0.7). No specific mutation was shown to significantly impact survival (table). Conclusions: Use of NGS technology in characterizing the genomic profile of patients with locally advanced or metastatic UC was feasible in most cases. Oncogenic variants were detected in the majority of patients, and more than half of them harbored a potentially "druggable" target, which may lead to future therapeutic advances.[Table: see text]
Comprehensive metabolomic profiling of plasma from patients (pts) with metastatic urothelial carcinoma (mUC) receiving immune checkpoint inhibitors (ICI) or platinum-based chemotherapy (PBC).
Authors: El Zarif Talal , Adib Elio , Clish Clary , Shukla Sachet A. , Freeman Dory , Thomas Jonathan , Ravi Praful , Tuff Martha , McGregor Bradley Alexander , Mantia Charlene , Ravi Arvind , Sonpavde Guru P. 
Published: February 2022

565 Background: Metabolomic profiling of plasma from mUC pts has not been comprehensively examined. Plasma metabolomics may capture the effects of interactions between the malignancy, host and therapy. We hypothesized that Identifying metabolites in plasma from patients with mUC receiving an ICI or PBC may shed valuable insights regarding tumor biology and mechanisms of resistance. Methods: We obtained 0.2 ml plasma before and after starting therapy from pts with mUC receiving an ICI or PBC at the Dana-Farber Cancer Institute. Plasma metabolomic profiling was conducted at the Broad Institute using 3 complementary liquid chromatography tandem mass spectrometry (LC-MS)-based metabolomics platforms. We measured 648 metabolites at baseline prior to starting ICI/PBC and at a second time point in each subject following initiation of ICI/PBC. Metabolite levels were assumed to be normally distributed with log transformation to transform distributions to be approximately symmetric. We performed Wilcoxon-rank sum test to compare the levels of metabolites before and after initiation of the ICI or PBC (significance at p < 0.05). Results: Plasma was available at baseline and during therapy in 53 mUC pts (ICI: n = 43; PBC: n = 10). The median age was 68 (range: 39-86) years and 42 (82.3%) were male. The median time from baseline to the second time point was 4.7 months (range: 0.7-90.2). The ICIs administered were atezolizumab (n = 20), pembrolizumab (n = 16), nivolumab (n = 5), and durvalumab + tremelimumab (n = 1). We identified 20 metabolites that were significantly increased in post-PBC plasma samples (vs. pre-PBC) and 19 metabolites increased in post-ICI (vs. pre-ICI) samples (p < 0.05). All altered metabolites except one (Uracil) were exclusive for each treatment group. The most significant metabolites that increased following initiation of the ICI and PBC are shown in the Table. Evaluation of the association of plasma metabolomics with clinical outcomes and toxicities is ongoing. Conclusions: This is the first report, to our knowledge, of comprehensive metabolomic plasma profiling of pre- and post-ICI and PBC pts with mUC. The metabolomic changes after ICI appear distinct from those seen after PBC. Furthermore, our study sheds insights on potential mechanisms of resistance and new therapeutic targets in pts with mUC.[Table: see text]