bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABLE: single-arm trial of nab-paclitaxel with ANTI-PD1 in advanced urothelial cancer.
Authors: Brown Jason , Daignault Stephanie , Reichert Zachery R. , Palmbos Phillip Lee , Alva Ajjai Shivaram 
Published: February 2020

520 Background: Anti-PD1 immune checkpoint inhibitor monotherapy is standard in cisplatin ineligible advanced urothelial cancer (aUC) patients (pts) that is PDL1 positive as well as in platinum refractory aUC. Nab-paclitaxel (Abraxane) monotherapy showed an overall response rate (ORR) of 27.7% in platinum refractory aUC. We conducted a single-arm trial of nab-paclitaxel and pembrolizumab in platinum refractory or cisplatin ineligible aUC (NCT03240016). Methods: Eligible pts had RECIST 1.1 measurable disease, grade 1 or lower neuropathy and adequate organ function. Study therapy consisted of nab-paclitaxel at starting dose of 125 mg/m2 IV on days 1 and day 8 and pembrolizumab 200 mg IV on day 1 in 21-day cycles until progression, intolerable toxicity, death or consent withdrawal. Primary endpoint was ORR by RECIST 1.1criteria. Secondary endpoints included safety/toxicity, progression free survival, overall survival, complete response proportion, duration of response (DOR) and duration of therapy (DOT). Results: Seventeen pts were enrolled between 02/2018 to 04/2019; 16 were response evaluable. Seven were of upper tract origin, 14/17 men, mean age 70.9 yrs (52 – 83), 71% pure urothelial, 8/17 platinum refractory; 9/17 cisplatin ineligible by Galsky criteria, and ECOG PS was 0, 1 or 2 in 6, 8 and 3 pts respectively. Unconfirmed ORR was 9/16 (56.25%: 95% CI [30-80%]), confirmed in 7; 14 pts experienced some tumor shrinkage; 2 pts had CR and 7 pts PR. Median DOR was 18 wks (95% CI: 6-NR) and median PFS 5.4 m (95% CI: 3.9-5.7). Pts received a median 6 cycles (range 1-11) with median DOT 4.4 m (0.7-7.6). Median follow up was 5.1 m. Grade ≥3 adverse events (AE) occurred in 15/17 pts including fatigue (n=5), peripheral neuropathy (n=3), anemia (n=3) and oral mucositis (n=3). Five pts had immune mediated AEs including 1 encephalitis; 5 pts discontinued treatment due to AEs, all attributed to nab-paclitaxel. Conclusions: The combination of nab-paclitaxel and pembrolizumab in advanced urothelial cancer exhibited promising activity but with moderate toxicity. A follow-up expansion study with nab-paclitaxel starting dose at 100 mg/m2 in 19 additional pts is being initiated. Correlative studies including PD-L1 expression and TILs are underway. Clinical trial information: NCT03240016.
Radiographic predictors of pathologic response to neoadjuvant chemotherapy with gemcitabine and cisplatin in patients with high-grade upper tract urothelial carcinoma.
Authors: Wong Nathan Colin , Ghafoor Soleen , Vargas Hebert Alberto , Bajorin Dean F. , Coleman Jonathan 
Published: February 2020

522 Background: Neoadjuvant chemotherapy (NAC) has established survival benefits prior to radical cystectomy for bladder cancer, yet its role in upper tract urothelial carcinoma (UTUC) prior to nephroureterectomy (NU) is less clear. We performed a phase II clinical trial of NAC with gemcitabine and cisplatin (GC) in patients with UTUC to evaluate pathologic response. We investigated if radiographic responses could predict pathologic response. Methods: Patients with high-risk localized UTUC (high grade on biopsy and/or radiographic evidence of cT2-4 disease with positive select cytology) were recruited to receive 4 cycles of GC prior to NU with the primary objective of the phase 2 study being pathologic response rate, defined as ≤pT1N0. All patients underwent CT imaging at before and after chemotherapy. All baseline imaging studies were categorized as: (i) no abnormality, (ii) focal mass or (iii) thickening without discrete mass. Post-chemotherapy imaging studies were categorized as: (i) stable disease, (ii) progression of disease, (iii) partial response or (iv) complete response. Radiographic responses were correlated with final pathologic staging. Results: 43 patients (pT0N0 = 9, ≤pT1N0 = 18 and >pT1N0 = 16) had CT performed pre- and post-chemotherapy. All patients had a visible lesion seen (mass = 34 and thickening = 9). The median pre-chemotherapy mass size was 3.1cm (IQR 1.8, 4.1). Approximately 60.5% of patients (N = 26) had evidence of hydronephrosis prior to chemotherapy. Following chemotherapy, 10 patients had a complete response, 20 had a partial response and 13 had stable disease. No patients progressed radiographically while on chemotherapy. Patients who had a complete radiographic response were more likely to have a pathologic response (≤pT1N0 = 90%), compared to a partial response (90% vs 65%, P = 0.21) and stable disease (90% vs 38%, P = 0.01). Conclusions: Radiographic response following NAC for UTUC appears to be correlated with pathologic response at time of surgery. Radiographic response, in addition to other pre-operative predictors, may play a useful role in counselling and optimizing management of patients with UTUC.
Feasibility of digital pathology of circulating tumor cells with morphologic analysis in localized bladder cancer.
Authors: Chalfin Heather , Harris Kelly , Glavaris Stephanie , Gorin Michael A. , Kates Max , Kearney Megan , Jendrisak Adam , Fong Megan , Matoso Andres , Johnson Michael Hiroshi , Pienta Kenneth J. , Hoffman-Censits Jean H. , Valera Vladimir , Apolo Andrea B. , Bivalacqua Trinity , Hahn Noah M. , McConkey David James 
Published: February 2020

525 Background: Circulating tumor cells (CTCs) are promising biomarkers in metastatic urothelial cancer (UC). Unfortunately, efforts in localized disease have been unsuccessful, in part due to limitations of existing technologies that rely on counting cells and epithelial-marker expression. Here, we applied a novel selection-free digital pathology platform in a localized UC cohort. To date, this platform has associated CTC morphology with differential therapeutic response in metastatic UC and castrate-resistant prostate cancer. If feasible in localized UC, we may potentially identify best candidates for adjuvant therapy or bladder sparing, as well as enable sensitive monitoring for recurrence. Methods: N=16 consecutive UC pts included 8 (50%) metastatic controls and 8 (50%) localized (3 (37%) at TURBT and 5 (63%) at cystectomy). Peripheral blood was processed with the Epic CTC platform (pan-CK/CD45/PD-L1/DAPI staining). Approximately 3 million cells per slide were imaged. Unsupervised clustering categorized CTCs into 5 subtypes based on 11 morphologic features (nuclear solidity, speckling, nucleoli and entropy; cytokeratin speckling and ratio; and cytoplasmic/nuclear circularity, area, and convex area ratio). Results: 119 CTCs were detected from 11/16 (69%) pts (5/8 (63%) localized (2 NMIBC, 6 MIBC) and 6/8 (75%) metastatic). All MIBC pts had cystectomy (4/6 (67%) received NAC). 2/8 (25%) metastatic pts had stable disease, 3/8 (38%) were progressing, and 3/8 (38%) had newly detected M1. Median (range) CTC count/mL was similar for localized and metastatic pts (0.4 (0-58.6), 0.75 (0-1.9)). CTCs were detected in a pt with CIS, but not in a pt with TaHG disease. 1/16 (6.3%) pts had a single PD-L1+ CTC. CTCs were successfully assigned into 5 subtypes with predominant features of large, small, or linear cells, high cytoplasmic circularity, and prominent nucleoli. Conclusions: Digital pathology and subtype assignment of CTCs is feasible in localized UC. Ongoing efforts at our center include application of this technology in localized patients receiving investigational checkpoint inhibitor therapy to potentially predict best responders or conversely those at the highest risk for recurrence.
Health-related quality of life (HRQoL) patient-reported outcomes (PROs) and survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: David Lorente , Lozano Rebeca , de Velasco Guillermo , Romero-Laorden Nuria , Castro Elena , Rodrigo-Aliaga Miguel , Sanchez Angel L. , Di Capua Carlos , Sanchez-Hernandez Alfredo , Olmos David 
Published: February 2020

53 Background: HRQoL is a relevant endpoint in trials in advanced prostate cancer. An association between HRQoL and OS has been reported. The Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a validated HRQoL PRO in mCRPC. Methods: We evaluated the association between FACT-P and OS in the COU-301 and COU-302 trials (abiraterone vs placebo in mCRPC pts). FACT-P scores, sub-scores (physical (PWB), emotional (EWB), functional (FWB), social (SWB) well-being, prostate cancer subscale (PCS) FACT-G and the Trial Outcome Index (TOI) were calculated. A decrease in 3 (PWB, EWB, SWB, FWB, PCS), 9 (FACT-G, TOI) or 10 (FACT-Total) points after 3 cycles was considered clinically relevant. The association between FACT-P and OS was evaluated with Kaplan-Meier, Cox-regression models and c-indices. Results: 2,177 pts (COU-301: 1,121 /COU-302: 1,056) had valid baseline (BL) FACT-P scores. Mean BL score was 106.6 (COU-301) and 122.3 (COU-302). BL total scores were associated with OS in both COU-AA-301 (p<0.001) and COU-302 (p<0.001), independent of treatment. All FACT-P sub-scores except SWB were associated with OS (Table). A decrease in FACTP scores was associated with decreased OS in COU-301 (19.6 vs 14.2m; HR: 1.8; p<0.001) and COU-302 (34.4 vs 27.7m; HR: 1.3; p=0.009) datasets. Conclusions: BL FACTP scores (except SWB subscale) are significantly associated with outcome. Early declines in HRQoL can be observed and are associated with worse outcome. Prospective evaluation of the significance of changes in HRQoL is needed. YODA Project 2018-3745.[Table: see text]
Comprehensive immune profiling of patients (pts) with metastatic urothelial cancer (mUC) or renal cell cancer (mRCC) receiving immune checkpoint inhibitors (CPIs).
Authors: Lavoie Jean-Michel , Nissen Michael , Baichoo Priya , Nappi Lucia , Khalaf Daniel Joseph , Kollmannsberger Christian K. , Chi Kim N. , Weng Andrew , Eigl Bernhard J. 
Published: February 2020

532 Background: CPIs have had a major impact on pts with mUC and mRCC. Only a small subset of pts benefit from CPI, and predictive biomarkers are needed. The role of circulating immune cells is poorly understood, but early changes after CPI exposure may predict response. We aimed to study the changes in circulating immune cell populations of pts receiving CPIs. Methods: Whole blood was collected prior to, and 3 wks after initiation of CPI in CPI-naïve pts with mUC or mRCC. PBMCs were isolated and profiled using mass cytometry (CyTOF) to provide a comprehensive overview of immune cell populations, expression of immune checkpoints, proliferation, and viability. Expression of chemokine receptors and cytokines was measured by flow cytometry. Treatment-emergent changes were correlated with response. Effects of treatment were determined by Wilcoxon signed-rank test; interactions of treatment and other variables like cluster size were determined by repeated measures two-way ANOVA. Any effects described had a significance of p<0.05. Results: Ten pts enrolled in this pilot study (mRCC = 4, mUC = 6) received anti-PDL1 (n=5), anti-PDL1/anti-CTLA4 (n=3), and anti-PDL1/chemotherapy (n=2). Best response was: 1 CR, 3 PR, 2 SD, 4 PD. Treatment induced an increase in dendritic cells (DC) and a decrease in PD1+ CD4+ and CD8+ T-cells. Elevated Ki-67, CTLA-4, LAMP-1, granzyme B and perforin expression in PD1+ cells post CPI suggested re-invigoration of exhausted T-cells. PD1+ T-cells had increased expression of the chemokine receptors CCR4 and CCR5, and decreased expression of CCR7 and CXCR4, irrespective of treatment. Response was associated with fewer CCR4+ CD4+ T cells and fewer PD1+ CD8+ T cells. Conclusions: Deep profiling by CyTOF provides a means of immune monitoring, with potential applications in clinical trials involving CPIs. Immune responses to CPIs are heterogeneous, with pt subgroups segregated by shifts in both T cell and DCs, and patterns of chemokine receptors and cytokines. Therapy reinvigorates exhausted T cells, and may cause these cells to infiltrate tumors or tumor-draining lymph nodes via chemokine receptors.
Genomic determinants of nested variant urothelial carcinoma.
Authors: Clinton Timothy Nguyen , Whiting Karissa , Silva Vitor , Li Qiang , Almassi Nima , Pietzak Eugene , Bagrodia Aditya , Cha Eugene K. , Dalbagni Guido , Iyer Gopa , Bochner Bernard H. , Arcila Maria E. , Ostrovnaya Irina , Gopalan Anuradha , Chen Ying-Bei , Fine Samson , Tickoo Satish , Reuter Victor E. , Solit David B. , Al-Ahmadie Hikmat 
Published: February 2020

538 Background: Nested variant urothelial carcinoma (NVUC) is a historically aggressive variant of bladder cancer with management reliant on radical cystectomy given unclear effectiveness of chemotherapy. Given the aggressive behavior of NVUC, the identification of pathogenic and potentially targetable genomic alterations could suggest novel treatment paradigms for this rare histologic variant. Methods: Query of our institutional database identified 81 cases of clinically localized NVUC. Each case was re-reviewed by GU pathologists to confirm the histology. Targeted capture sequencing was performed to define the spectrum of genomic alterations in known and putative cancer genes. Clinical and sequencing data was then compared between the nested variant cases and a prospective cohort of clinically localized high-grade urothelial carcinomas, not otherwise specified (UC NOS). Results: On central re-review, tumors were classified as either classic NVUC (N=53) or high-grade urothelial carcinoma with nested features (N=28). A cohort of UC NOS patients (N=600) was used as a comparator. Median follow-up of the overall cohort was 4.3 years. Classic NVUC was associated with higher risk of cancer specific mortality compared to UC NOS on multivariate analysis (HR 1.76, p=0.04). Tumor mutational burden was lower in classic NVUC tumors versus UC NOS. Evaluation of 136 cancer-associated genes identified differences in mutational frequencies across the 3 cohorts (Table) with RhoA and FOXA1 alterations enriched in NVUC. Conclusions: Patients with NVUC have significantly higher risk of cancer specific mortality than patients with UC NOS. While there was significant overlap between the landscape of genomic alterations in NVUC and UC NOS tumors, NVUC tumors were enriched for RhoA and FOXA1 alterations among others.[Table: see text]
Rapid organoid development, drug screening, and neoadjuvant chemotherapy response prediction for patients with locally advanced bladder cancer.
Authors: Kaffenberger Samuel D. , Brown Jason , Merrill Nathan , Marchetti Kathryn , Bao Li Wei , Cheng Xu , Udager Aaron M. , Herrel Lindsey A. , Vandecan Nathalie , Montgomery Jeffrey S. , Hafez Khaled , Weizer Alon , Morgan Todd Matthew , Alva Ajjai Shivaram , Soellner Matthew , Merajver Sofia 
Published: February 2020

543 Background: Neoadjuvant chemotherapy prior to radical cystectomy (RC) for muscle-invasive urothelial carcinoma (UCCx) is the standard of care though the absolute survival benefit is small, and some patients progress during chemotherapy. While progress has been made in the prediction of sensitivity to platinum-based chemotherapies, providing more accurate, personalized, and clinically-relevant chemotherapy response prediction is an unmet need. We present our early and ongoing experience with rapid, organoid-based drug-screening. Methods: one gram of tumor was procured from patients undergoing TURBT or RC and divided between DNA/RNA sequencing, organoid drug-screening, and patient-derived xenografts. Tissue was dissociated, filtered, and resuspended in organoid media for serial passage and drug screening. Drugs were tested at “Cmax” concentration, which is the maximum plasma concentration in human trials so as to provide physiologic relevance. Results were normalized to control such that a value of 100 indicated no drug effect compared to control, and a value of 0 indicated complete response. Number of drugs screened was dependent upon tissue available, but was often 20-30. Results: 25 patients have undergone rapid organoid development and drug testing to date. Clinical correlations with chemotherapy response are ongoing. Drug response analyses were available 5-10 days following procedure. Select drug response data from the 9 most recent patient organoid samples are presented in the Table. DNA and RNA sequencing and PDX models are in progress. Conclusions: This platform allows for the rapid determination of neoadjuvant chemotherapy response and may further guide selection of therapeutic agents in patients with locally advanced bladder cancer.[Table: see text]
A methodological comparison of mapping algorithms to obtain health utilities derived using cross-sectional and longitudinal data: Secondary analysis of NRG/RTOG 0415.
Authors: Khairnar Rahul Ramesh , DeMora Lyudmila , Sandler Howard M. , Lee W. Robert , Villalonga Olives Ester , Mullins C. Daniel , Bruner Deborah , Shah Amit , Malone Shawn , Michalski Jeff , Dayes Ian , Seaward Samantha A. , Albert Michele , Currey Adam D. , Pisansky Thomas Michael , Chen Yuhchyau , Horwitz Eric M. , DeNittis Albert S. , Feng Felix Y , Mishra Mark V. 
Published: February 2020

55 Background: To compare the predictive ability of health utility mapping algorithms derived using cross-sectional and longitudinal data specific to the Expanded Prostate Cancer Index Composite (EPIC). Methods: This mapping study utilized data from an international, multicenter, randomized controlled trial of patients with low-risk prostate cancer conducted by NRG Oncology (NCT00331773). Health-related quality-of-life (HRQoL) data were collected using EPIC, and health utilities were obtained using EuroQOL-5D (EQ5D) at baseline and 6, 12 and 24 months post-intervention. Data were split into an estimation sample (70%) and a validation sample (30%). Ordinary Least Squares (OLS) regression models were estimated using baseline cross-sectional data as well as pooled data from all assessment periods. Random effects (RE) specifications that explicitly model the longitudinal nature of the data were also estimated. Candidate models were selected based on root mean square error (RMSE). Results: A total of 196 (147) patients in the estimation sample had complete EQ5D and EPIC domain (subdomain) data at all time points. OLS models using combined data outperformed the counter-part RE models as well as OLS models using baseline data in the five-fold cross-validation. Addition of covariates to the models resulted in improved predictive ability. In the external validation, when only EPIC domain/ subdomain data are available, the OLS model using combined data predicted EQ5D utilities better than the counterpart RE model and OLS model using baseline data (RMSE=0.121108 & 0.111345). OLS model using baseline data outperformed other model types for algorithms with EPIC domains and demographics (RMSE=0.121757), while RE models outperformed the other two model types for algorithms with EPIC subdomains and demographic data, (0.112782) and for algorithms with EPIC domains/ subdomains, demographics, and clinical covariates (RMSE=0.123589 & 0.163093). Conclusions: While algorithms using pooled data outperformed other model types in internal validation, RE models showed better predictive ability in external validation for algorithms with covariates. Clinical trial information: NCT00331773.
Discordance of HER2 expression in distant metastatic tumors (MTs) versus primary tumors (PTs) in urothelial carcinoma (UC).
Authors: Grigg Claud , Livasy Chad , He Jiaxian , Hartman Aaron , Clark Peter E. , Raghavan Derek , Burgess Earle Frederick 
Published: February 2020

550 Background: Available HER2 targeted agents have limited benefit for UC, but exceptional tumor responses are occasionally seen. HER2 expression has been tested as a biomarker of response to these drugs. Trial eligibility is often based on HER2 expression in PTs. Previous studies found moderate to high concordance of HER2 expression in PTs and synchronous regional nodes at cystectomy, but the concordance rate with distant MTs is poorly defined and further complicated by shifting definitions of HER2 positivity. Methods: Immunohistochemical (IHC) staining for HER2 (Ventana Pathway clone 4B5) was performed on PTs and matched MTs in 79 patients with UC. IHC staining was scored (0-3+) using intensity and % positive tumor cells using 2018 ASCO/CAP guidelines for breast cancer. Fisher’s Exact Test assessed association of PT and MT HER2 scores, and Cohen’s kappa statistic (κ) assessed agreement in HER2 3+ between groups. MTs were defined as synchronous if biopsied <60 days after the PT biopsy. Results: There were 67 metachronous and 12 synchronous paired biopsies; median time between metachronous biopsies was 418 days. MT biopsy sites included lymph node (30%), bone (22%), lung (18%), pelvic/peritoneal soft tissue (11%), liver (8%), brain (4%), other (6%). HER2 2+ and 3+ expression was seen in 30.4% and 12.7% of PTs and 12.7% and 7.6% of MTs, respectively. Of HER2 3+ PTs (n=10), HER2 expression in paired MTs was 0 (n=3), 1+ (n = 3), 2+ (n = 2), and 3+ (n = 2). Of HER2 3+ MTs (n=6), HER2 expression in paired PTs was 0 (n=1), 2+ (n=3), and 3+ (n=2). An association was observed between PT and MT HER2 scores (p=0.004), however there was low agreement of HER2 3+ rates between PT and MT lesions (κ = 0.17, p=0.113). Discordance was noted in both synchronous and metachronous biopsies. Conclusions: Based on the current HER2 3+ definition, HER2 overexpression is spatially and temporally discordant in UC between PTs and distant MTs. These findings suggest that both PTs and MTs should be tested for HER2 expression in future clinical trials assessing the efficacy of HER2 targeted agents in UC. The high discordance may explain previously negative therapeutic studies.