bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy of two cycles of neoadjuvant chemotherapy for upper tract urothelial carcinoma patients.
Authors: Zennami Kenji , Takahara Kiyoshi , Fukaya Kosuke , Ichino Manabu , Fukami Naohiko , Sasaki Hitomi , Sumitomo Makoto , Kusaka Mamoru , Shiroki Ryoichi
Published: February 2020

505

Background: Upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with poor prognosis. However, the efficacy of neoadjuvant chemotherapy (NAC) and optimal No. of NAC cycles for UTUC have been poorly defined. In this study, we evaluated if two cycles of NAC improves survival of UTUC patients in our institute. Methods: A total of 167 patients who underwent radical nephroureterectomy at Fujita Health University between November 2005 and December 2018 were retrospectively analyzed. The study group comprised 114 patients with UTUC who received NAC followed by surgery. The control group consisted of 53 patients who underwent initial surgery without NAC. We compared two groups in overall survival (OS), cancer specific survival (CSS), recurrence free survival (RFS, urinary tract, visceral) and independent prognostic factors. Kaplan-Meier methods, log-rank test and cox proportional-hazards models were used for statistical analysis. Results: Median follow up was 1108 days, and there were no significant differences in preoperative patient characteristics between NAC group and initial surgery (IS) group. NAC had significantly improved 5-year OS (75% vs 55%, p=0.004) and 5-year CSS (84% vs 65%, p=0.024). That is more significant in the analysis with cT3 patients (p=0.0002). NAC also significantly improved visceral RFS (p=0.001). However, NAC does not affect urinary tract RFS (p=0.96) when compared to IS. pDS were observed in 55 out of 114 (48%) in NAC group, and 12 out of 53 (22%) in IS group. Comparison of OS between with pDS and without pDS demonstrated significantly better OS in with pDS group (p=0.0001). Multivariate cox proportional-hazards models identified NAC, pDS, resection margin, pN and cT3 as independent prognostic factors for OS. Conclusions: Two cycles of NAC induced pDS and improved survival of UTUC patients. Reduced number of NAC cycles may offer clinical benefits of low chemo-associated toxicity, appropriate surgery without delay in chemo-resistant case and sufficient cancer regression with pDS.
Prospective trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Zaghloul Tarek , Smith Andrew , Abdalla Ahmed , Khaled Hussein Mustafa , William Hany , Hwang Wei-Ting , Baumann Brian Christopher
Published: February 2020

515

Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemo or decline it. Adjuvant radiotherapy (RT) is an alternative (or complementary) adjuvant therapy, but is rarely performed, with most of these patients being observed. In a prospective trial, we compared RT vs adjuvant chemo & hypothesized that RT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial at the National Cancer Institute (Cairo) compared adjuvant RT (standard of care in Egypt) vs. chemo+RT after RC for LABC. A 3rd arm, adjuvant chemo, was added later (gemcitabine/cisplatin x 4). Herein, we report results of RT vs adjuvant chemo. Patients ≤70 y/o with ≥1 of the following (pT3b/T4a, grade 3 or pN+) with negative margins after RC were eligible. RT was delivered with 3-D conformal RT to the pelvis (45 Gy in 1.5 Gy BID). Routine follow-up & pelvic CT q 6 months were performed. Post hoc non-inferiority exploratory analysis was performed. Results: 123 were enrolled (78 RT/45 chemo). 51% had urothelial carcinoma; 49% had squamous cell carcinoma. The arms were well-balanced except for gender (p=0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for RT vs chemo were 54% vs 47% for DFS [HR 0.65(95%CI 0.35-1.19, p=0.16]; 92% vs 69% for local-regional recurrence-free survival [HR 0.28(95%CI 0.10-0.82), p=0.02]; 75% vs 79% for distant metastasis-free survival [HR 2.39(95%CI 0.94-6.09), p=0.07]; 61% vs 60% for overall survival [HR 0.94(95%CI 0.52-1.69), p=0.83]. In the urothelial cohort, there were no differences in DFS or OS. Late grade ≥3 GI toxicity was observed in 6 RT patients (8%) & 1 chemo patient (2%). Based on our data, there is a >90% probability that the true difference in 2-year DFS is <10%, the prespecified non-inferiority margin. Conclusions: This prospective study demonstrates that adjuvant RT has superior local control vs adjuvant chemo with no statistically significant differences in DFS or OS. Results suggest that RT can be an option for patients with LABC after RC where an alternative to chemo is desired by the patient or physician. Clinical trial information: NCT01734798.
Alvimopan as an essential component of ERAS protocol to decrease length of hospital stay.
Authors: Hanna Peter , Kalapara Arveen , Regmi Subodh , Srujana Kalyana , Zabell Joseph , Randle Darrel , Kaizer Alexander , Patten Luke , Konety Badrinath R. , Wahr Joyce , Weight Christopher J.
Published: February 2020

517

Background: Radical cystectomy for muscle invasive bladder cancer is the gold standard. However, it is frequently associated with a prolonged length of hospital stay (LOS). We study the effect of ERAS protocol implementations and Alvimopan use in patients undergoing radical cystectomy and its impact on length of hospital stay (LOS). Methods: Retrospective cohort study involving consecutive patients undergoing radical cystectomy for bladder cancer at our institution from 2010 through 2018. We evaluated Alvimopan use plus an ERAS protocol post radical cystectomy versus patients who underwent ERAS protocol alone versus those who were managed prior to ERAS protocol implementation. Primary outcome of interest was LOS, controlling for age, sex, smoking status and Charleson comorbidities index. Results: 146 patients (49.32 %) received standard care (non-ERAS) (group A), 102 patients (34.45 %) underwent ERAS protocol alone (group B) and 47 patients (15.87 %) underwent ERAS protocol plus Alvimopan (group C). There was no significant difference in length of stay between group A and group B (p=0.856). However, group C experienced a shorter LOS (16.6%) compared to group A (p=0.015). Similarly, group B was not significantly associated with the days to bowel movements compared to group A (p=0.112), however, group C demonstrated a significantly shorter time (16.3%) to bowel movements compared to group A (p=0.015). On other hand, group c wasn’t significantly associated with time tolerance to regular diet (p=0.068). Limitations include retrospective nature of some of the data, non-randomized approach and confounders such as a mix of robot and open approaches to cystectomy. Conclusions: Of all ERAS protocol components, Alvimopan appeared to be the most significant contributor in accelerating GI recovery and decrease LOS in our cohort.
Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with advanced urothelial carcinoma.
Authors: Beom Seung-Hoon , Rha Sun Young , Ahn Joong Bae , Shin Sang Joon
Published: February 2020

519

Background: Immune checkpoint inhibitors (ICI) are active in patients with advanced urothelial carcinoma which progressed to platinum-based chemotherapy. Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in several cancer types. Here we evaluated whether PD-1/PD-L1 inhibitors affect the antitumor effects of SCT after ICI in patients with urothelial carcinoma. Methods: A retrospective study was conducted at Yonsei Cancer Center. Eligibility criteria were patients who received at least one SCT as 3rd-line or beyond, following progression after platinum-based chemotherapy and ICI and for whom efficacy data were available between January 2017 and September 2019. We evaluated efficacy outcomes to each therapy, including ORR by RECIST version 1.1, progression-free survival (PFS), and overall survival (OS). Results: In total, 35 patients met the inclusion criteria and were included in the analyses. ICIs were given as monotherapy and they were administrated as second-line in 48% and as later line in 52%. Twenty-six patients (74%) received a anti-PD-L1 inhibitor and 9 (26%) did a anti-PD-1 inhibitor. SCT included single paclitaxel (60%), MVAC (26%), gemcitabine/platinum combination (9%), and pemetrexed (6%). The ORR to SCT was 26%. Among 9 patients who received MVAC, 5 (55.5%) achieved a partial response. Median progression-free survival was 2.5 months and median overall survival was 7.8 months. A number of prior chemotherapy regimens was associated with response to SCT on univariate analysis. Conclusions: In urothelial cancer patients, the confirmed ORR (26%) to SCT after ICI exposure was higher as compared to historical data from the pre-ICI era. These data indicate that anti–PD-1/PD-L1 inhibitors could make tumors more vulnerable to subsequent chemotherapy.
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.
Clinicopathological features and their impacts on the prognoses of patients with nonurothelial carcinoma: A hospital-based cancer registry in Japan.
Authors: Nagumo Yoshiyuki , Kojima Takahiro , Kojo Kosuke , Kimura Tomokazu , Kandori Shuya , Kawai Koji , Okuyama Ayako , Higashi Takahiro , Nishiyama Hiroyuki
Published: February 2020

555

Background: Urothelial carcinoma (UC) is the most common histology of genitourinary (GU) tract cancer. Non-UC tumors in the GU tract appear to be more aggressive than UC at that location, but the clinicopathological features and their impacts on the prognoses of the non-UC patients are not known due to the low numbers of these patients. Methods: We used Hospital-Based Cancer Registry (HBCR) data in Japan to extract non-UC cases, i.e., patients with adenocarcinoma (AC), squamous cell carcinoma (SCC), or small cell carcinoma (SmCC) of the GU tract who were diagnosed in 2008–2009 with histological confirmation and had received first course of treatment. We retrospectively analyzed the clinicopathological features of these patients, stratified by the bladder and the upper urinary tract (UUT) as tumor locations. We used a Cox proportional hazards regression to identify prognostic factors associated with the overall survival (OS). Results: Of the 8,095 cases at the bladder and 2,580 cases at the UUT, 384 (4.7%) and 131 (5.1%) non-UC cases were identified, respectively. The proportions of histologic subtypes in the bladder were 1.7% AC, 2.4% SCC, and 0.7% SmCC. In the UUT group, these proportions were 1.3%, 3.4%, and 0.4%, respectively. At both tumor locations, the distribution of ages was similar across all subtypes, with the age peak in the 70s. More patients with non-UC were diagnosed at an advanced clinical stage compared to the patients with UC at either location. The 5-yr OS rates of the non-UC patients with a tumor in the bladder and at the UUT were 40% and 26%, whereas the corresponding 5-yr OS rates among the UC patients were 61% and 52%, respectively. A multivariate analysis revealed that the presence of non-UC was significantly associated with increased mortality (hazard ratio 1.66, 95% confidence interval 1.48–1.87) regardless of the tumor location. Conclusions: The clinicopathological features of the non-UC patients were similar between both tumor locations. The presence of non-UC was associated with poor prognosis regardless of the tumor location. A standard of care must be established for non-UC patients, since the prognoses of these patients are not satisfactory.
Variance in symptom assessment between patient and caregiver: A prospective study of patients staged as metastatic prostate cancer—An interim analysis.
Authors: Swift Sadie , Vitin Jane , Prime Hillary , Topp Robert , Dato Paul , Cohen Edward , Gaylis Franklin
Published: February 2020

56

Background: Closely monitored and managed patient reported outcomes (PROs) can impact survival of cancer patients. However, the reliability and validity of patients’ self-reported symptoms are somewhat open to question, as past studies have shown that patients may underreport health information to their physicians. Identifying where the discrepancy between PROs and actual symptomology lies may be important in improving providers’ grasp of a patients’ disease state. The purpose of this study is to compare prostate cancer patients’ reports of their symptoms and functioning with the patients’ caregivers’ perception of the same factors. Methods: 50 patients with metastatic prostate cancer on Androgen Deprivation Therapy (ADT) and their caregivers were asked to independently complete the Functional Assessment of Cancer Therapy- Prostate (FACT-P), Brief Pain Inventory- Short Form (BPI-SF), and EQ-5D-3L questionnaires in relation to the patient’s condition. Patient and caregiver dyad responses to these instruments were then compared by t-tests for continuous measures and Chi-Square for discrete measures. Results: Not all patient and caregiver dyads completed all of the data collection instruments. Patients are more likely than caregivers to rate themselves as having fewer limitations on mobility (n=47, p≤0.001), less pain and/or discomfort (n=46, p≤0.001), and less limitations with self-care (n=46, p≤0.001). Furthermore, caregivers were more likely to rate patients as having more anxiety (n=47, p≤0.001), more severe pain (n=20, p<0.05), and lower overall physical wellbeing scores (n=40, p<0.005). Ratings for emotional and social functioning were not significantly different between the patient and their caregiver. Conclusions: Overall a high degree of agreement was reported between patient and caregiver ratings of the patient’s symptoms and functioning; however, when differences were present the caregivers consistently rated the patients’ conditions as more severe, particularly in relation to physical symptoms. This may indicate that patients are minimizing their symptoms when reporting to their physicians.
Association of baseline modified Glasgow Prognostic Score (mGPS) with survival outcomes in patients with metastatic urothelial cell carcinoma (mUCC) treated with immune checkpoint inhibitors (CPI).
Authors: Brown Jacqueline T , Liu Yuan , Shabto Julie M. , Martini Dylan J. , Ravindranathan Deepak , Hitron Elise , Russler Greta , Caulfield Sarah , Yantorni Lauren Beth , Joshi Shreyas S. , Kissick Haydn , Ogan Kenneth , Harris Wayne , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: February 2020

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Background: The mGPS, a clinical tool that incorporates albumin and C-reactive protein, has proven useful in the prognostication of multiple cancers. Several CPI agents have been approved for the treatment of mUCC but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in mUCC patients receiving CPI. Methods: We retrospectively reviewed mUCC patients treated with CPI (PD-1 or PD-L1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of CPI until death or clinical/radiographic progression, respectively. mGPS was defined as a summary score with one point given for CRP > 10 mg/L and/or albumin < 3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model for OS and PFS. Results: A total of 53 patients were included with a median follow up 27.1 months. The median age was 70 years with 84.9% male and 20.8% black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. The correlation between mGPS and other inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR), was high with Pearson correlation coefficients ≥ 0.48 (p ≤ 0.0003). Increased mGPS at the time of CPI initiation was associated with poorer OS and PFS (Table). Conclusions: The mGPS may be a useful prognostic tool in mUCC patients when treatment with CPI is under consideration. These results warrant a larger study for validation.[Table: see text]
Molecular characterization of advanced muscle invasive bladder cancer (MIBC): Comparison of low-input targeted RNA sequencing (RNAseq) strategies.
Authors: Shibata Yoichiro , Uronis Joshua M. , Conroy Jeffrey M. , Glenn Sean , Guo John , Mayhew Gregory , Eisner Joel Robert , Milburn Michael Vance
Published: February 2020

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Background: 5-year survival for advanced MIBC is poor (~5%), but newer targeted agents (e.g., PD-1/PD-L1 or FGFR) have improved survival over traditional chemotherapy. To better select patients suited for targeted therapies, molecular characterization is more important than ever. The following study compares RNAseq using two low-RNA-input methods (SureSelect hybridization-capture and AmpliSeq PCR amplification, using 200 ng and 10 ng extracted RNA, respectively), as part of a retrospective study of advanced MIBC patients treated with anti-PD-1/PD-L1 therapy (Mayhew et al, 2019 ASCO). RNAseq results, including correlation between methods and molecular subtype agreement are presented herein. Methods: RNA extracts from 24 representative FFPE MIBC tumor samples were analyzed using SureSelect XT RNA (Agilent) and AmpliSeq transcriptome (Illumina) by NovaSeq6000 paired end sequencing. Samples were split between 4 molecular subtypes using the GeneCentric 60-gene MIBC nearest centroid subtyper (n = 6/subtype; luminal, luminal infiltrated, basal, basal infiltrated) (Mayhew et al, 2019 ASCO). Pearson correlation analysis was performed for all genes, as well as the 60 suptyper genes. Expression subtype calls were compared using RNAseq data obtained from both sequencing methods. Results: Of 58,000 genes queried (GrCH38.v22), 27,671 (55%) were found using both methods and 13,992 (28%) were not found using either method. 15,575 unique genes were found using SureSelect and 1,149 unique genes were found using AmpliSeq. The two methods were well correlated: median of 0.87 (0.73-0.89) overall and 0.80 (0.54-0.86) for the 60 subtyper genes. 22 of the 24 samples (92%) had congruent subtype calls using the 60-gene MIBC subtyper; one luminal-infiltrated called basal and one basal called basal-infiltrated. Conclusions: This study demonstrated comparable RNAseq analysis using two low-input FFPE-compatible methods. Using AmpliSeq, MIBC tumors were able to be molecularly characterized, including subtype analysis, with only 1/20th of the extracted RNA needed for SureSelect. Further validation of AmpliSeq methodology in MIBC and other tumor types is warranted.
Racial disparities in the outcomes of transitional cell carcinoma of the bladder: A population-based analysis.
Authors: Baidoun Firas , Ruhban Inas A. , Saad Anas M. , Gad Mohamed M. , Jazieh Khalid , Al-Husseini Muneer J. , Ornstein Moshe Chaim , Rini Brian I. , Gupta Shilpa
Published: February 2020

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Background: Bladder cancer is the most common type of genitourinary malignancy and is the fourth most common cancer in men in the US. Transitional cell carcinoma (TCC) of the bladder accounts for most bladder cancer cases. Previous studies have observed racial disparities in the prognosis between white and black populations with very little mentioned about other ethnicities and race groups that are part of the United States population. We hereby, present a detailed and comprehensive analysis of racial disparities in TCC survival in the US. Methods: Using the data from surveillance Epidemiology and End results (SEER) database, we identified patients with TCC between 1992 and 2015. We used multivariable covariate-adjusted Cox models to analyze the overall and TCC-specific survival of patients according to their race. Results: We evaluated 176,388 patients with TCC and after we adjusted for age, sex, race, stage, grade, and undergoing cancer-targeted surgery, we found that Asians/Pacific Islanders and Hispanics had a better overall survival when compared to whites (HR= 0.792, 95% CI [0.761-0.824], P<.001 and HR = 0.941, 95% CI [0.909-0.974], P = .001, respectively). Asians/Pacific Islanders also showed better TCC specific survival (HR = 0.843, 95% CI [0.759-0.894], P<.001). Blacks had worse overall survival and TCC-specific survival (HR =1.221, 95% CI [1.181-1.262], P <.001 and HR =1.325, 95% CI [1.268- 1.384], P <.001, respectively). When stage IV TCC was analyzed separately, only Hispanics showed better overall and TCC specific survival when compared to whites (HR = 0.896, 95% CI [0.806-0.997], P = 0.044 and HR = 0.891, 95% CI [0.797-0.996], P = 0.42). Conclusions: Asians/Pacific Islanders have better overall and TCC-specific outcome while blacks have the worst outcome compared to whites. Hispanics have better overall and cancer specific survival in stage IV TCC. These disparities likely related to different and complex factors from lifestyle and chemical exposure to genetic factors. Further studies can help us more in understanding and approaching this malignancy in different race groups.
Characteristics of radiation-associated bladder cancer compared to primary bladder cancer
Authors: Sha Sybil , Dee Edward Christopher , Mahal Brandon Arvin Virgil , Mouw Kent William , Nguyen Paul L. , Muralidhar Vinayak
Published: February 2020

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Background: Radiation-associated muscle-invasive bladder cancer (RA-MIBC) has been suggested to represent a more aggressive disease variant compared to primary (non-radiation associated) MIBC. We sought to characterize the presentation, patterns of care, and outcomes of RA-MIBC compared to primary MIBC. Methods: We identified 60,117 patients diagnosed with non-metastatic or metastatic MIBC between 1988 and 2015 using the Surveillance, Epidemiology, and End Results (SEER) database and stratified patients based on whether radiation had been administered to a pelvic primary prior to the development of bladder cancer. We used logistic regression to compare rates of chemotherapy, surgery, or radiation for patients with RA-MIBC compared to primary MIBC. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC and primary MIBC. Results: There were 1,093 patients with RA-MIBC and 59,024 patients with primary MIBC. Patients with RA-MIBC were older compared to patients with primary MIBC (mean age 77.4 years vs 72.4 years, p < 0.001) and more likely to be male (86.8% vs 73.3%, p<0.001). RA-MIBCs were more likely to be high-grade (57.5% vs 47.6%, p<0.001), more likely to have T4 disease at diagnosis (21.0% vs 17.3%, p<0.001), and less likely to be node-positive (4.2% vs 8.1%, p < 0.001). In terms of treatment, non-metastatic primary MIBC patients were more likely to undergo radiation (14.0% vs 3.1%, p<0.001) as well as radiation with cystectomy (1.9% vs 0.8%, p<0.001) compared to those with RA-MIBC. Median survival was significantly shorter for patients with RA-MIBC (13 mo. vs 19 mo.; p<0.001). Conclusions: RA-MIBCs tend to present with higher grade and higher stage disease and are less likely to receive curative treatment. Even when adjusting for stage, grade, and receipt of treatment, patients with RA-MIBC have worse survival compared to those with primary MIBC. These findings raise the possibility that RA-MIBC represents a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand biological differences between RA-MIBC and primary MIBC and develop improved therapeutics for radiation-associated cancers.
Oncological outcomes following radical cystectomy for urothelial carcinoma of the bladder with positive lymph nodes.
Authors: Ladi Seyedian Seyedeh Sanam , Bateni Zhoobin , Pearce Shane , Ghodoussipour Saum , Nazami Azadeh , Cai Jie , Miranda Gus , Bhanvadia Sumeet , Djaladat Hooman , Schuckman Anne K. , Daneshmand Siamak
Published: February 2020

584

Background: To determine oncological outcomes among patients who underwent radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder with positive lymph nodes (LN). Methods: On a retrospective review of 4093 patients from our institutional IRB approved cystectomy database from Jan 1971 to Dec 2017, we identified 3284 patients who underwent RC for UC of the bladder. We included patients with positive LNs at the final pathology. The data was stratified into three groups based on number of positive LNs: 1, 2-9, and more than 10 positive LNs. Multivariable analysis was performed to identify prognostic factors for overall survival (OS) and recurrence-free survival (RFS). A subgroup analysis was performed to assess the oncological outcomes in cases that did not receive any chemotherapy (adjuvant or neoadjuvant). Results: 712 patients (22%) had positive LN after RC. Median age was 68 years and 76% of patients were male. 105 (15%) patients had clinical evidence of LN involvement on pre-operative imaging. Patient characteristics are provided in Table. Five-year (5-y) RFS for 1, 2-9 and 10+ positive LNs was 39%, 36% and 16%, respectively (p<0.001). 5-y OS were 45%, 33% and 14%, respectively (p<0.001). On multivariable analysis, more than 10 positive LNs pathologic tumor stage >pT2, and neoadjuvant chemotherapy were associated with increased risk of recurrence and worse overall survival after radical cystectomy. Adjuvant chemotherapy was associated with decreased risk of recurrence and better overall survival after radical cystectomy. On subgroup analysis of patients with positive LNs without peri-operative chemotherapy, 5-y RFS for 1, 2-9 and 10+ positive LNs was 25%, 32% and 5%, respectively (p<0.001). 5-y OS was 31%, 20% and 4%, respectively (p<0.001). Conclusions: Only 15% of patients with positive LNs have clinical evidence of LN involvement prior to cystectomy. Oncological outcomes after radical cystectomy are associated with the number of involved LNs. Surgery alone can be curative in 20-30% of patients with less than 10+ LN.