bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of Bacillus Calmette-Guérin (BCG) Therapy on prognosis in patients with carcinoma in situ (CIS) of the upper urinary tract: A retrospective comparison with nephroureterectomy.
Authors: Yoneyama Takahiro , Soma Osamu , Suzuki Yuuichiro , Yoneyama Tohru , Mori Kazuyuki , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Hashimoto Yasuhiro , Ohyama Chikara
Published: March 2019

417

Background: Clinical benefit of bacillus Calmette-Guérin (BCG) therapy for the management of upper urinary tract carcinoma in situ (CIS) remain unclear. We investigated safety and long-term oncological outcome of BCG therapy for upper urinary tract CIS compared with nephroureterectomy. Methods: We treated consecutive 490 patients with upper urinary tract carcinoma Aomori, Japan. We retrospectively reviewed the post-treatment course of 60 patients with CIS of the upper urinary tract who had undergone either a radical nephroureterectomy (RNU group) or BCG therapy (BCG group). Clinical effectiveness, safety, and oncological outcomes were compared between the groups. Multivariate Cox regression analysis via inverse propensity treatment weighted (IPTW) methods was performed to identify the impact of BCG therapy on prognosis. Results: The number of patients in RNU and BCG groups were 22 and 38, respectively. Median follow-up was 59 months in this cohort. There was no significant difference in background of patients including age, sex, performance status between the groups. The reason of selection for BCG therapy were bilateral CIS of upper urinary tract (50%), solitary kidney (26%), and others (24%). The cytology became negative in 30 (79%) patients after 6-week course of BCG. BGC related adverse events were observed 92% of patients. Most common events were cystitis (76%) followed by fever (50%). Two patients experienced grade 3 sepsis after BCG therapy. 13 patients (43%) experienced tumor recurrence after BCG therapy. There were no significant differences in recurrence-free survival, cancer-specific survival, and overall survival between the RNU and BCG groups. Multivariate analysis revealed BCG therapy did not worse the prognosis of those patients. Conclusions: Although mild adverse events were frequented in BCG therapy for CIS of the upper urinary tract, it might be a useful alterative in patients with CIS of the upper urinary tract who are ineligible for radical nephroureterectomy. Further prospective studies are needed to confirm the benefits of BCG therapy for CIS of the upper urinary tract.
Randomized phase I trial of pembrolizumab with neo-adjuvant versus concomitant stereotactic body radiotherapy in metastatic urothelial carcinoma: Clinical and translational results.
Authors: Vandekerkhove Gillian , Sundahl Nora , Decaestecker Karel , Meireson Annabel , De Visschere Pieter , Fonteyne Valerie , De Maeseneer Daan Joost , Reynders Dries , Goetghebeur Els , Van Dorpe Jo , Verbeke Sofie , Annala Matti , Brochez Lieve , Van der Eecken Kim , Wyatt Alexander William , Rottey Sylvie , Ost Piet
Published: March 2019

422

Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). The trial was approved by the Ethical Committee of Ghent University Hospital and is registered on ClinicalTrials.gov (NCT02826564). Funding was provided by Merck Sharp & Dohme. Results: Eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4-5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Conclusions: Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution and suggests a shared driver gene status throughout disease progression. Clinical trial information: NCT02826564.
Predictive role of CT texture analysis in patients with metastatic urothelial cancer treated with PD-1/PD-L1 inhibitors.
Authors: Alessandrino Francesco , Gujrathi Rahul , Nassar Amin , Alzaghal Arwa , Ravi Arvind , McGregor Bradley Alexander , Sonpavde Guru , Shinagare Atul B.
Published: March 2019

424

Background: Reliable biomarkers to predict response of urothelial cancer to PD-1/PD-L1 inhibitors are still being investigated. Texture analysis represents underlying tumor heterogeneity and may serve as a predictor of response in urothelial cancer. The purpose of this study was to assess predictive ability of CT texture analysis for disease progression in patients with metastatic urothelial cancer treated with PD-1/PD-L1 inhibitor. Methods: In this IRB-approved HIPAA-compliant retrospective study, from total 93 consecutive patients with metastatic urothelial cancer treated with PD-1/PD-L1 inhibitors from 2013-2018, 43 patients with measurable disease per RECIST 1.1 criteria who had contrast-enhanced CT performed within three months after starting treatment were included. Progression-free survival was calculated based on serial follow-up CTs, and 11 patients without progression who did not reach 1 year follow-up were excluded. Texture features of measurable lesions on first follow-up CT were extracted (TexRAD Ltd, Feedback Plc, Cambridge, UK). Stepwise logistic regression analysis to identify patients who had progressive disease (PD) at 12 months was performed and performance assessed using receiver operator curves. Results: Of 32 included patients (24 men, 8 women; median age: 65 years) who had total 80 measurable lesions, 22 progressed by 12 months. On first follow-up CT, the entropy and mean of the lesions were higher (p = 0.04, p = 0.02) for patients with PD by 12 months. Calculated specificity and sensitivity of entropy (AUC = 0.79) were 90%, and 63%; of mean (AUC = 0.81) were 90%, and 50%. A predictive model including mean and entropy yielded 95% sensitivity, 80% specificity, 91% PPV, 89% NPV and 91% accuracy (AUC = 0.863) to identify patients with PD at 12 months. Conclusions: Texture analysis of CT performed within three months after starting PD-1/PD-L1 can help predict patients who progress by 12 months with high accuracy. Further studies investigating the correlation of texture analysis with survival endpoints may help validate the role of texture analysis as a biomarker to predict response to PD1/PD-L1 inhibitors.
Avelumab treatment for metastatic urothelial carcinoma in the phase Ib JAVELIN Solid Tumor Study: Updated safety and efficacy analysis with ≥ two years of follow-up.
Authors: Apolo Andrea B. , Ellerton John Allan , Infante Jeffrey R. , Agrawal Manish , Gordon Michael S. , Aljumaily Raid , Britten Carolyn D. , Dirix Luc , Lee Keun-Wook , Taylor Matthew H. , Schoffski Patrick , Wang Ding , Ravaud Alain , Xiong Junyuan , Rosen Galit , Gulley James L. , Patel Manish R.
Published: March 2019

425

Background: Avelumab, a human anti‒PD-L1 IgG1 antibody, is approved for the treatment of metastatic urothelial cancer (mUC) progressing after platinum chemotherapy in the US, Canada, and Israel. Here, we report an updated pooled analysis of 2 cohorts of avelumab-treated patients (pts) with mUC from the JAVELIN Solid Tumor study (NCT01772004). Methods: Pts with mUC whose disease had progressed after platinum-based therapy or were cisplatin ineligible received avelumab 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (NCI CTCAE v4.0). Results: As of April 2018, 249 pts had received avelumab and had been followed for ≥2 years (median 2.7 years). Median treatment duration was 12.0 weeks (IQR, 6.0-32.1), and 12 pts (4.8%) remained on treatment. Confirmed ORR in all evaluable pts (n = 242) was 16.5% (95% CI: 12.1%-21.8%; complete response in 4.1%). Median DOR was 20.5 mo (95% CI: 9.7-not estimable), and the Kaplan-Meier (K-M) estimate of 12-mo DOR was 65.4% (95% CI: 47.0%-78.8%). Median PFS was 1.6 mo (95% CI: 1.4-2.7 mo), median OS was 7.0 mo (95% CI: 5.9-8.5 mo), and the K-M 12-mo and 24-mo OS rates were 35.9% (95% CI: 29.9%-42.0%) and 20.1% (95% CI: 15.2%-25.4%), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 71.1% of pts (177/249), most commonly infusion-related reactions (24.1%), fatigue (18.1%) and rash (18.1%). Grade ≥3 TRAEs occurred in 11.6% of pts (29/249), most commonly fatigue (1.6%), elevated lipase (1.6%), and pneumonitis (1.2%). Ten pts (4.0%) discontinued avelumab due to a TRAE. There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab showed durable clinical activity and had a manageable safety profile in pts with mUC. A phase 3 trial of avelumab in the maintenance setting after first-line platinum-based therapy for mUC is ongoing. Clinical trial information: NCT01772004.
Avelumab treatment in metastatic urothelial carcinoma: Association between early response and durable outcomes in the phase Ib JAVELIN Solid Tumor Study.
Authors: Patel Manish R. , Gulley James L. , Lee Keun-Wook , Infante Jeffrey R. , Manitz Juliane , Kasturi Vijay , Zhang Hao , Rosen Galit , Apolo Andrea B.
Published: March 2019

429

Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, avelumab treatment in post-platinum patients (pts) has shown promising and durable antitumor activity and favorable overall survival (OS) outcomes. Here, we report post hoc analyses to assess if early response to avelumab is associated with long-term treatment outcomes. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). A Kaplan-Meier subgroup analysis has been performed for duration of response (DOR); response by week 7 (first tumor scan ± 5 days) define balanced subgroups. A landmark analysis was used to assess the association between time-to-response and OS. The landmark was 3 mo (second tumor assessment; 12 weeks ± 5 days). Results: 242 pts with platinum-treated mUC received avelumab and were followed up for ≥2 years (median, 2.7 years; data cutoff, Apr 2018). No difference in DOR was found between pts who had responded by the first tumor assessment (n=15) and those who responded later (n=25; HR, 0.8 [95% CI: 0.3-2.0]). In a landmark analysis for OS, the median OS was not reached (NR [95% CI: 18.9 mo-NR]) in pts who had responded within 3 mo (n=29) compared with 9.5 mo (95% CI: 6.5-14.4) in pts with late response or stable disease (n=74), and 4.3 mo (95% CI: 2.8-7.1) in other pts (progressive disease [PD] or not evaluable; n=70). Further sensitivity analyses found that survival did not vary between pts who continued treatment beyond investigator-confirmed PD (n=46) vs those that did not (n=24; median survival, 5.0 mo [95% CI: 2.8-8.8] vs 4.3 mo [95% CI: 0.9-8.3], respectively). Conclusions: Responses to avelumab have similar durability irrespective of time to response. Pts with an early response to avelumab tend to survive longer than pts with stable disease, and both groups have longer OS than nonresponders. Clinical trial information: NCT01772004.
The cost of obesity in radical cystectomy.
Authors: Huynh Melissa , Wang Ye , Pucheril Daniel , Zlatev Dimitar V. , Chang Steven Lee , Mossanen Matthew , Yu Alice
Published: March 2019

434

Background: The Centers for Disease Control and Prevention estimates that nearly 40% of the U.S. population meets the criteria for obesity classification. Several studies have shown that obesity is associated with increased medical morbidity and costs. In this study, we investigated the impact of obesity on the financial burden of radical cystectomy. We hypothesize that the cost of radical cystectomy is greater in obese and morbidly obese patients compared to overweight patients. Methods: We performed a retrospective observational study within the Premier Healthcare Database (Premier Inc., Charlotte, NC), a large, U.S. hospital-based, all-payer database representing approximately 20% of annual inpatient discharges. ICD-9 procedure codes were used to identify all patients who had undergone elective radical cystectomy (57.71, 57.79) from 2003 to 2015, and administrative data was used to extract the costs associated with the index hospitalization. Patients were stratified into three body mass index (BMI) categories: overweight (25 BMI <30), obese (30 ≤ BMI < 40) and morbidly obese (BMI ≥ 40). Quantile regression analysis was performed to examine the effect of BMI category on cost. Results: We identified 12,056 patients who underwent radical cystectomy, 1,406 of whom had data available regarding BMI category. The crude cost of the index hospitalization for radical cystectomy was $24,596 for overweight patients. The costs associated with patients in the obese and morbidly obese categories were $2,158 ( p=0.059) and $5,308 ( p<0.001) higher compared to overweight patients, respectively. Median operative time for overweight, obese, and morbidly obese patients was 346, 391, and 420 minutes, respectively (p=0.0001). Multivariable models were constructed controlling for clinicodemographic, and surgical factors. After adjustment for operative time, there were no longer any statistically significant differences in cost between the BMI categories. Conclusions: The cost of radical cystectomy is significantly greater for obese and morbidly obese patients compared to overweight patients. This increased financial cost associated with obesity difference is driven by increased operative times encountered in obese patients.
Neoadjuvant chemotherapy utilization in muscle-invasive bladder cancer: Increasing yet inappropriate use?
Authors: Nyame Yaw A. , Holt Sarah K , Winters Brian , Psutka Sarah P. , Dash Atreya , Schade George R , Lin Daniel W. , Yu Evan Y. , Gore John L. , Wright Jonathan L.
Published: March 2019

441

Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is associated with improved overall survival in patients with muscle-invasive bladder cancer (MIBC); however, utilization nationally has been low. Over the past decade, the use of NAC has increased to approximately 20% of patients with MIBC. We investigate whether this increase in NAC is with appropriate cisplatin-based regimens using registry data. Methods: This is a population-based analysis of linked SEER-Medicare data from 2004-2011. We identified 4,534 patients with cT2-4N0-1 bladder cancer undergoing cystectomy. Specific chemotherapy drugs administered were identified using pharmacy records. The cohort was stratified into three groups, standard of care (SOC: i.e., appropriate cisplatin-based chemotherapy), non-SOC, and no NAC. Descriptive statistics were performed to compare each group and multivariate logistic regression performed to determine factors associated with receiving SOC NAC. Results: Over the study period, 694/4534 (15.3%) of patients in the study received NAC, increasing from 11.0% in 2004 to 24.8% in 2011. From 2004-2011, 345/694 (49.7%) of patients who were given NAC received a non-SOC regimen. Among patients that received non-SOC NAC, the most common regimens included gemcitabine-carboplatin in 170/345 (49.3%), gemcitabine monotherapy 73/345 (21.2%) carboplatin monotherapy in 51/345 (14.8%), cisplatin monotherapy 29/345 (8.4%), and MVA with carboplatin 3/345 (0.8%). On multivariate analysis, age (OR 0.91[95% CI 0.88-0.94]) and moderate/severe renal disease (OR 0.2[95% CI 0.08-0.51]) were negatively associated with SOC NAC. The year of diagnosis (OR 1.32[95% CI 1.23-1.42]) was positively associated with the receipt of SOC NAC in the cohort. Conclusions: Although NAC for MIBC has increased, nearly half of these patients are not receiving SOC cisplatin-based regimens. This underscores the importance of better identifying patients eligible for neoadjuvant therapy, the need for appropriate drug selection which may be facilitated through centers of excellence and multidisciplinary clinics, and the need for more clinical trials for cisplatin ineligible patients.
Hyperprogressive disease in patients with metastatic genitourinary tumors treated with immune checkpoint inhibitors.
Authors: Suárez Cristina , Morales-Barrera Rafael , Garcia-Ruiz Alonso , Gonzalez Macarena , Ligero Marta , Valverde Claudia , Serrano Cesar , Mateo Joaquin , Perez-Lopez Raquel , Carles Joan
Published: March 2019

448

Background: Hyperprogressive disease (HPD) is a new pattern of progression in cancer patients (pts) treated with immune checkpoint inhibitors (ICI). The rate and outcome of HDP in pts with metastatic renal carcinoma (RCC) and urothelial carcinoma (UC) are unknown. Here, we report the percentage of HPD in a cohort of pts with GU malignancies treated at our center and explore associations with clinical variables. Methods: Medical records from pts treated in phase I-III clinical trials with ICI alone or in combination between July 2013 and June 2018 were retrospectively reviewed. We defined HPD according to the radiologic VHIO´s criteria (ASCO 2018). Associations between HPD and categorical or continuous variables were evaluated using Fisher exact test and Wilcoxon test respectively. OS were estimated with the Kaplan-Meir method. Statistical analyses were performed using the R statistical software (R version 3.5.0). Results: Overall, 104 pts received therapy with ICI. Of these patients, 16 were not included for the analysis (6 pts with absence of measurable disease, 6 pts did not have CT scan available after the clinical progression and 4 pts treated with ICI plus chemotherapy). Thus, 88 pts were included for the analysis, 29 (33%) with RCC and 59 (67%) with UC. Median follow-up was 7.4 months. Median age was 66.5 years (range 29-91 y).Twenty-three pts (26%) were treated with ICI monotherapy and 65 pts (74%) in combination (anti-CTL4, antiangiogenics, PARP inhibitors, FGFR inhibitors). Forty-seven pts (53%) received ICI as second-line therapy or later. By RECIST v1.1, 26 (30%), 19 (21%) and 43(49%) pts had a best response of progressive disease, stable disease or partial+complete response, respectively. We identified 9 pts (10%) who meet the HPD criteria, 2 pts with RCC and 7 with UC. HPD was associated with anemia at baseline (p = 0.058). Pts with HPD had a trend toward lower overall survival (OS) compared with pts with non-HPD (8.87 vs 4.77 months; p = 0.065). Conclusions: These findings demonstrate that HPD is a phenomenon seen in a significant proportion of pts with RCC and UC and should be taken in account. We found that HPD is associated with poor OS and the anemia at baseline was correlated with HPD.
Does tumor location affect prostate cancer prognosis?
Authors: Akatsuka Jun , Kimura Go , Obayashi Kotaro , Sano Masayuki , Yanagi Masato , Endo Yuki , Takeda Hayato , Hayashi Tatsuro , Matsuzawa Ichiro , Suzuki Yasutomo , Hamasaki Tsutomu , Kondo Yukihiro
Published: March 2019

45

Background: Does tumor location affect prostate cancer prognosis? To clarify this question we conducted a retrospective study to characterize the incidence and prognostic significance of tumor location of prostate cancer. Methods: From 2000 to 2017, radical prostatectomy with no neoadjuvant therapy was performed in 916 cases in our hospital. Serial whole mount sections were reviewed to determine the incidence, clinicopathological features and prognostic significance of tumor location in the prostate gland. For the tumor location, we defined the subzones, which were made from subdivision of the McNeal’s zonal anatomy, are shown in Table 1 in detail. The peripheral zone (PZ) is composed of 8 subzones including A1, A2, A3 , M1, M2, M3, M4, M5. The transition zone (TZ) is composed of 5 subzones including T1, T2, T3, T4 and B1. The central zone (CZ) is composed of 3 subzones including M6, B2 and B3. Results: The median age was 67 and PSA was 8.6 ng/ml. The subzonal tumor incidence divided by all cases was the highest in A2, followed by M4, A1, M3, T2 in that order, while the lowest in B3, followed by M6, T4, T3, B1 in that order. The median follow-up time was 67 months. A 5-year PSA failure rate (5Y-PSAFR) was 23%. Among the subzones, the highest 5Y-PSAFR was seen in B3, followed by M6, B2, T4, A3, and the lowest was seen in M4, A2, T2, A1 in that order. A multivariate analysis for PSAF risk among subzones showed that B3 (HR 8.6, p <0.0001) and M6 (HR 3.3, p = 0.03) were the independent high risk subzones. Conclusions: We demonstrated that the cancer incidence and prognosis varies according to the location within the prostate gland. The B3 and M6 around the ejaculatory duct showed the lowest incidence, while these locations also had the highest recurrence risk. [Table: see text]
Metabolic syndrome and upper tract urothelial carcinoma: A retrospective analysis from a large Chinese cohort.
Authors: Xu Hang , Tan Ping , Yang Lu , Wei Qiang
Published: March 2019

452

Background: Metabolic syndrome (MetS) has been reported to be associated with poor survival outcomes in cancer patients. However, the role of MetS in upper tract urothelial carcinoma (UTUC) has yet to be explored. We aim to investigate the prognostic value of MetS in UTUC after radical nephroureterectomy (RNU). Methods: A total of 644 patients with UTUC after RNU were identified at West China Hospital from May 2003 to December 2016. MetS was defined as the co-existence of three or more of five components (obesity, hypertension, elevated fasting glucose, decreased high-density lipoprotein-cholesterol and hypertriglyceridemia). Logistic and Cox regression analyses was performed to evaluate the associations of MetS with pathological features and survival outcomes. Decision curve analysis was performed to determine the clinical utility of the prediction models. Results: Of 644 patients, 157 (24.4%) had MetS. Over a median follow-up of 39 months, 269 (41.8%) experienced disease recurrence, 233 (36.2%) died and 185 (28.7%) died of UTUC. MetS was independently associated with high-grade disease (odds ratio [OR]: 2.01, P = 0.005), advanced pT stage (≥ pT3, OR: 1.54, P = 0.027) and lymphovascular invasion (OR: 1.71, P = 0.03). Multivariate Cox regression analysis showed that MetS was an independent factor for decreased cancer-specific survival (CSS, HR: 1.38, 95% CI: 1.01-1.89, P = 0.042) but not for RFS (HR: 1.27, 95% CI: 0.97-1.67, P = 0.078) and OS (HR: 1.24, 95% CI: 0.95-1.62, P = 0.121). The estimated c-index of the multivariate models for CSS was 0.763 compared with 0.769 when MetS added. Conclusions: MetS is a negative prognostic factor in UTUC. Further studies of MetS in UTUC are demanded.
Genomic concordance between profiling of circulating tumor DNA (ctDNA) and matched tissue in metastatic urothelial carcinoma.
Authors: Vandekerkhove Gillian , Lavoie Jean-Michel , Annala Matti , Sundahl Nora , Sano Takeshi , Struss Werner J. , Todenhöfer Tilman , Ost Piet , Chi Kim N. , Black Peter C. , Eigl Bernhard J. , Wyatt Alexander William
Published: March 2019

457

Background: Biomarkers are urgently needed to facilitate tumor molecular stratification in metastatic urothelial carcinoma (mUC), thus potentially enabling patient selection for targeted- and immuno-therapies. We aimed to assess concordance for clinically-relevant driver gene alterations between same-patient tumor tissue and ctDNA. Methods: Whole blood samples were collected from 90 mUC patients (162 samples in total) for next-generation sequencing of cell-free DNA (cfDNA) and leukocyte DNA. Deep targeted sequencing was performed across a custom 50 bladder cancer gene panel (median cfDNA depth of 986x). Matched archival primary tissue and/or metastatic tissue biopsy was available from 65 patients, and profiled using the same assay. Results: 81% of mUC patients (73/90) had ctDNA fractions above 2% in at least one blood collection (median ctDNA fraction 22%). A high tumor mutation burden (≥25 mutations per Mb) was observed in ctDNA from 20 patients (27%). From ctDNA, TP53 and ARID1A were mutated in 64% and 29% of patients, respectively. Tissue from distant metastatic lesions was available from 17 patients; 82% (62/76) of coding somatic mutations identified were independently detected in the matched ctDNA sample; however, 7/14 discordant calls were attributable to the paired sample having a low ctDNA fraction. Similarly, 89% (88/99) of coding somatic mutations detected in archival primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. Sequencing multiple sites from archival cystectomies revealed spatially and genomically distinct subclones in 2/4 cases. Conclusions: In mUC, tumor tissue and ctDNA demonstrate remarkably high concordance; our findings support the use of either approach in the characterization of truncal driver gene alterations.
Fibroblast growth factor receptor status and response to immune checkpoint inhibition in metastatic urothelial cancer.
Authors: Rose Tracy L , Hayward Michele C , Salazar Ashley H , Eulitt Patrick , McGinty Katrina , Drier Anthony , Wobker Sara Elizabeth , Whang Young E. , Brower Blaine Y , Dunn Mary , Crona Daniel James , Shibata Yoichiro , Uronis Joshua M , Mayhew Gregory , Milowsky Matthew I. , Kim William Y.
Published: March 2019

458

Background: Fibroblast growth factor receptor (FGFR) inhibitors are a promising new targeted therapy for patients with metastatic urothelial cancer (UC) and FGFR alterations. FGFR-altered tumors are more likely to be of the luminal molecular subtype, which is less immune infiltrated and may be less likely to respond to immune checkpoint inhibitors (ICP). Methods: Metastatic UC patients at the University of North Carolina who underwent targeted exon sequencing (any CLIA-certified platform) and were treated with ICP since 2014 were identified. Patients with any FGFR alteration were compared to patients without alterations (including mutations, fusions, and amplifications in FGFR1-4). Overall response rates (ORR) to ICP were assessed by a radiologist (K.M.) per RECIST 1.1 and compared between FGFR-altered and unaltered tumors using Fisher’s exact tests. Patients who died prior to radiologic assessment were considered non-responders. Results: 66 patients (median age 70, 65% male, 76% white, 21% black) were identified. Most patients (74%) had received prior platinum-based chemotherapy, and 13% had received 2 or more prior lines of therapy. At the time of initiation of ICP, 32% of patients had a hemoglobin < 10, 33% had liver metastases, and 72% had a performance status > 0. Fifteen (22%) patients had FGFR alterations. The ORR for all patients was 15%, with ORR of 13% in FGFR-altered patients compared with 16% in unaltered patients (p = 1.0). No patients (0/9, 0%) with known pathogenic mutations in FGFR3 responded to ICP compared to 10/57 (18%) of patients without these alterations (p = 0.33). 46% of FGFR-altered patients who stopped ICP due to progression received subsequent therapy. Conclusions: Response rates to ICP are low and there was no difference in ORR between FGFR-altered and unaltered patients. While no patient with pathogenic FGFR3 mutations responded to ICP in our cohort, this difference did not reach statistical significance. Given low response rates overall, some FGFR-altered patients may benefit from treatment with FGFR inhibitors prior to ICP. Analysis of larger cohorts of patients as well as patients from clinical trials and more in-depth molecular profiling may add further clarity.
Assessment of the androgen receptor (AR) activity score versus AR expression in muscle invasive bladder cancer (MIBC).
Authors: Bergerot Paulo Gustavo , Arvinitis Leonidas , Dizman Nazli , Salgia Meghan , Pal Sumanta K. , Jones Jeremy
Published: March 2019

463

Background: Previous studies have demonstrated that a considerable proportion of BCs express androgen receptor (AR), and that AR might drive tumor growth. The RNA-based AR activity score is a novel analytic tool that may better quantify the functional role of AR. Methods: Samples were obtained from patients (pts) with MIBC who had cystectomy or transurethral resection of bladder tumor (TURBT). AR expression was quantified by pathologist scoring of immunohistochemistry (IHC). The AR activity score was quantified using RNA isolates from benign and cancerous sections of slides adjacent to those used for IHC. RT-qPCR of a panel of AR-regulated genes was performed with comparison of transcript levels to those in LNCaP prostate cancer cells. Clinical results were validated in the RT-112 cell line. Results: A total of 37 pts (81.8% male) were analyzed with a median of age of 67. The majority were diagnosed as cT3 (54.5%) and 62.2% underwent neoadjuvant chemotherapy (86.9% with cisplatin/gemcitabine). IHC demonstrated a range of AR positivity from 0.0% to 90.0%, with most samples (46.0%) having no staining. In contrast, the AR activity score was between 2.1% and 178.9% (relative to LNCaP cells) with a median activity of 32.2% in cancerous tissues and 44.0% in benign regions. AR expression and score showed no direct correlation. A strong association was seen between AR activity score in cancerous tissue and DFS (P = 0.005). Interestingly, AR score in benign tissue was inversely correlated with DFS (P = 0.04). Pts who received neoadjuvant chemotherapy were noted to less likely develop metastases (P = 0.05). A more marginal correlation was noted between AR activity score and pathologic downstaging. Treatment of cells transfected with an AR expression plasmid along with an AR-responsive luciferase reporter demonstrated a dose-dependent effect of cisplatin in this assay. Conclusions: IHC and AR activity scores represent independent measures in this MIBC cohort. Our study suggests that pts with higher AR activity may be more susceptible to chemotherapy, and may have prolonged DFS. Additional studies in larger cohorts are warranted.
Urine cell flow cytometry analysis of PD-L1 expression and DNA content for bladder cancer.
Authors: Chen Pin-I , Wang Alice (Xiaoyang) , Deebajah Mustafa , Alanee Shaheen , Patterson Bruce Kendrick
Published: March 2019

466

Background: Bladder cancer is the fifth most common cancer in the United States. PD-1/PD-L1, a pathway used by cancer cells to evade immune response, correlates with bladder cancer severity and has emerged as a target in bladder cancer treatment. Chromosomal instability is also a prominent feature associated with the development of bladder cancer. A method to unbiasedly analyze PD-L1 expression and DNA content in cells from urine samples will help us better understand bladder cancer. Methods: To evaluate the PD-L1 expression and DNA content, we developed a 4-color flow assay. Cells in urine samples were pelleted, fixed/permeabilized (in incellMAX, IncellDx Inc.) and stained with antibodies against pan-cytokeratin (CK), CD45, PD-L1 and a cell cycle dye. The stained samples were analyzed by a flow cytometer alongside stained control cells. Results: Fifty bladder cancer patient and 15 normal donor urine samples were collected and tested with this assay. We could distinguish epithelial cells (pan-CK+) and white blood cells (WBCs, CD45+) in urine samples and obtain PD-L1 expression and DNA content information simultaneously from these cell populations. The patient samples showed a significantly higher percentage of WBCs with substantial PD-L1 expression. The percentage of PD-L1 positive epithelial cells was not distinguishable between normal donor and patient samples. However, increased post G1 epithelial cells ( > 5%) were observed in a majority of bladder cancer patients, with around 25% of samples showing a DNA index above 1.05. In addition, a comparison of urine collection fixatives showed that incellMAX-fixed samples had the best single cell recovery and DNA content measurement, as shown by lower cell cycle dye staining variability (lower rCV). Statistically significant differences were found between cancer patients and normal samples. Conclusions: We developed a flow cytometry-based method to investigate PD-L1 and DNA content simultaneously in cells from urine samples. Comparing urine samples from bladder cancer patients and normal yielded statistically significant differences that could provide valuable information for bladder cancer patient management.
Sequential intravesical gemcitabine and docetaxel in the treatment of BCG-naive patients with non-muscle invasive bladder cancer.
Authors: Thomas Lewis , Steinberg Ryan , Nepple Kenneth Gerard , O'Donnell Michael A.
Published: March 2019

469

Background: Bacillus Calmette-Guerin (BCG) is the standard of care for patients with new non-muscle invasive bladder cancer (NMIBC) after transurethral tumor resection. While BCG has been compared to single agent intravesical chemotherapy as first-line therapy, few studies exist comparing BCG to sequential intravesical chemotherapy regimens. The objective of this work was to determine the efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in BCG naïve patients with NMIBC. Methods: Patients without prior BCG exposure who underwent Gem/Doce intravesical treatments were retrospectively identified. These patients had been treated with 6 weekly instillations of gemcitabine (1 gram of gemcitabine in 50 ml of sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Patients without recurrence then underwent maintenance therapy with monthly instillations for two years. Treatment success was defined as no bladder cancer recurrence and no cystectomy. Survival analysis was performed using the Kaplan Meier method. Results: 30 patients were treated with a median follow-up of 18 months. Eighty percent (n=24) of patients had high risk disease. Median age was 78 years old. The most common indications for Gem/Doce therapy were “advanced age/frailty” (n=15), “immunosuppression” (n=4), and “BCG Shortage” (n=4). Treatment success was 96% at 3 months, 89% at 1 year, and 89% at 2 years. No patients progressed or required cystectomy. Treatments were generally well tolerated, with only one patient unable to finish induction and two patients declining maintenance. Side-effects included urinary urgency/frequency (30%), dysuria (26%), and hematuria (23%). A need for dose reduction or delay was uncommon (16%). The all-cause mortality rate was 3.5% at 1 year, and 16.5% at 2 years. Neither bladder cancer nor the treatments were the cause of any of the deaths. Conclusions: Sequential intravesical gemcitabine and docetaxel is an effective treatment for BCG naïve NIMBC. Treatments are generally well tolerated even in a frail and comorbid patient population. Further evaluation of this combination therapy for BCG naïve disease is warranted.
Identification of gene expression determinants of radiosensitivity in bladder cancer (BCa) cell lines.
Authors: Sitalaximi Thirunavukkarasu , Vuong Winston , Balyimez Aysegul , Ganguly Shinjini , Lee Byron H , Stephenson Andrew J. , Haber Georges-Pascal , Day Mark L. , Tomlins Scott A. , Radivoyevitch Tomas , Lindner Daniel J. , Ornstein Moshe Chaim , Tendulkar Rahul D. , Stephans Kevin L. , Ciezki Jay P. , Grivas Petros , Mian Omar Y.
Published: March 2019

470

Background: Trimodality therapy with TURBT followed by concurrent chemoradiation is an alternative to cystectomy in selected patients with muscle invasive BCa. Identifying genetic determinants of radiation response may help select patient for organ-sparing treatments with curative intent. Methods: Molecular characterization of 20 cell lines was previously performed, including mutation analysis, CNA (high density SNP arrays) and gene expression (RNAseq). Cell line identity was authenticated by genomic fingerprinting. We performed colony forming assays (CFA) and cumulative survival was quantified using the area under the cell survival curve (AUC, range 0-8Gy) to create a radiosensitivity index. Pre and post-radiation proliferative capacity was determined by cell titer glo (CTG) assay. Gene (R v3.5.1) and network (Ingenuity Pathyway Analysis) level expression differences were determined as a function of AUC to identify biologically relevant associations with radiation response. Results: Of 20 cell lines (7 basal, 13 luminal subtype), both CFA and CTG data was successfully obtained for 13 cell lines (6 basal, 7 luminal) treated with high dose rate (HDR) radiation. AUCs for the colony forming assay (CFA) survival curves ranged 1.79-3.27. RNAseq identified 18,634 unique transcripts mapping to distinct loci and 196 genes were identified with AUC correlation p values <0.01 (FDR <0.5, mean FPKM>0.5). These genes were strongly enriched for membership in the peroxisome proliferator (PPAR) pathway (IPA, p = 9.40E-03) and STAT3 pathway (IPA, p = 1.56E-3). Validation studies confirmed PPARγ, ICAM2, JAK3, IL1B, OAS1 and OAS2 genes to be associated with differential response to radiation, with expression upregulated in radio-resistant cells. A basal subtype was strongly associated with a radiosensitive phenotype (Chi-Squared χ2 p=0.0083). Conclusions: BCa radio-sensitivity was associated with baseline gene expression differences in vitro. The basal subtype and repression of either the PPAR or STAT3 pathways predicted increased radiosensitivity. This study nominates candidate biomarkers for mechanistic studies and clinical validation in BCa.
Association between immune-related adverse events (irAEs) and clinical outcomes (CO) in advanced urothelial cancer patients (pts) treated with immunotherapy (IO).
Authors: Shabto Julie M. , Martini Dylan J , Liu Yuan , Ravindranathan Deepak , Kline Meredith R , Hitron Elise , Russler Greta , Caulfield Sarah , Kissick Haydn , Alemozaffar Mehrdad , Ogan Kenneth , Harris Wayne , Master Viraj A. , Carthon Bradley Curtis , Kucuk Omer , Bilen Mehmet Asim
Published: March 2019

472

Background: The increasing use of IO agents in the treatment of urothelial cancer has revealed irAEs during therapy. We investigated whether there is an association between treatment-related irAEs and CO in urothelial cancer pts treated with IO. Methods: We performed a retrospective analysis of 67 urothelial cancer pts treated with PD-1/PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were calculated from first IO dose to date of death or hospice referral and clinical or radiographic progression, respectively. Objective response (OR) was defined as partial or complete response per RECISTv1.1. Treatment-related irAEs were determined from clinic notes. The univariate association between irAE and clinical outcomes was generated using chi-square test and Fisher’s exact test. Results: The median age was 70 and 79.1% were men. 41.8% of pts had received 2 or more prior lines of therapy. Nine pts (13.4%) experienced irAEs including infusion reactions, rashes, and joint pain. Median follow-up from date of first dose of IO was 15 months (95% CI: 11-18 months). The overall death rate for pts who experienced irAE was 0%, while it was 62% for pts who did not experience irAE ( p<0.001) (Table). Conclusions: Experiencing irAEs was associated with lower death rate and progression rate and higher rate of OR in this cohort. These findings should be validated in a larger study. Univariate association of irAEs with CO. [Table: see text]
Impact of pure versus mixed metastatic urothelial carcinoma (mUC) histology on response with immune checkpoint inhibitors (ICIs).
Authors: Agarwal Archana , Nassar Amin , Pond Gregory Russell , Barletta Justine A. , Acosta Andres , Abou Alaiwi Sarah , Curran Catherine , Sonpavde Guru
Published: March 2019

479

Background: PD1/PD-L1 inhibitors have been evaluated in trials enrolling patients (pts) with pure urothelial or mixed urothelial histology containing non-urothelial components. However, any differential impact of pure vs. mixed urothelial histology on ICI benefit is unclear. We conducted a retrospective study to evaluate the impact of pure vs. mixed urothelial carcinoma histology on outcomes with ICIs in pts with metastatic urothelial carcinoma (mUC). Methods: We obtained data from 120 pts with mUC from a single institution (DFCI) who received ICI therapy. Demographic, clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. Histology was reviewed at DFCI for all pts and recorded as pure urothelial if only urothelial carcinoma was seen or mixed urothelial if components of any other histology were observed in addition to urothelial. A Cox regression analysis was done to study the association of prognostic variables and histology with objective response. Results: Data was obtained from 120 pts, of whom 110 (91.7%) received a single agent PD1/PD-L1 inhibitor (pembrolizumab=58, atezolizumab=52, nivolumab=4, nivolumab + ipilimumab=3, nivolumab + vaccine=2, durvalumab+tremelimumab=1). The median age was 66, 70.8% were male and 72.5% had received prior chemotherapy. 79 (65.8%) tumors originated from the bladder, 39 (32.5%) from the upper tract, 2 (1.67%) had unknown site of origin. 91 (76.6%) had pure urothelial and 28 (23.3%) had mixed urothelial histology. On univariable analysis, pure vs. mixed urothelial histology was not associated with response (HR 1.52 [95% CI 0.59-3.98, p=0.39]). On multivariable analysis, upper tract vs. bladder primary (HR 3.06 [95% CI 1.10-8.49], p=0.032) and higher blood neutrophil to lymphocyte ratio (HR 0.35 [95% CI 0.17-0.72], p=0.004) were associated with lower response rate. Conclusions: In this hypothesis-generating study, pure vs. mixed urothelial carcinoma histology did not appear to significantly impact response to ICI therapy for mUC. The impact of proportion of non-urothelial histology, pure non-urothelial histology and site of primary on response warrants further study.
Plasmacytoid variant urothelial carcinoma: Clinicopathologic outcomes and experience with neoadjuvant chemotherapy.
Authors: Ericson Kyle J , Thomas Lewis , Lee Byron H
Published: March 2019

483

Background: Plasmacytoid variant histology is a rare variant that is often locally advanced at diagnosis. Data is limited to small series and the ideal treatment remains unknown. Here we report the clinicopathologic features and outcomes of 29 patients with plasmacytoid variant histology, including 12 patients treated with neoadjuvant chemotherapy (NAC) and 4 with adjuvant or salvage immunotherapy. Methods: All cystectomies performed from 2011-2018 at our institution were reviewed. Patients with plasmacytoid features on transurethral resection or cystectomy were included. Categorical variables were compared using chi-squared tests and survival outcomes were analyzed with log-rank analysis. Results: A total of 993 patients underwent cystectomy for malignancy. Of these, 29 patients (2.9%) had plasmacytoid variant features. At cystectomy, 65.5% were ≥ pT3, 48.2% were node positive, and 13.8% had positive soft-tissue margins. Twelve patients died during the observed period (41.4%), with a median time to death of 7.2 months. Among surviving patients, median follow-up was 21.9 months. Of the 4 patients with positive margins, survival was significantly worse than those with negative margins (p<0.005); all 4 died with a median survival of 1.8 months. Cisplatin based NAC was given to 12 patients (41.4%). NAC was not associated with a survival benefit over cystectomy alone (median survival 27.7 and 51.9 months, respectively; p=0.07), complete response (pT0), or organ confined disease (< pT3). Four patients (13.8%) received adjuvant or salvage checkpoint inhibitors; all surviving with a median follow-up of 28.7 months. Conclusions: Consistent with prior reports, plasmacytoid variants were uncommon and locally advanced. While our rate of positive margins was lower than in previous series, patients with positive margins universally did poorly. NAC was not associated with improved survival or pathologic outcomes. Our findings suggest plasmacytoid variants may not respond well to NAC, though no definitive conclusions can be drawn due to the small number of patients and retrospective design.
Contemporary analysis of ureteroenteric strictures after open and robot-assisted radical cystectomy: A population-based study.
Authors: Patel Neal , Alshak Mark , Goh Alvin , Sedrakyan Art , Belarmino Andre , Sun Tianyi , Bochner Bernard H. , Hu Jim C.
Published: March 2019

484

Background: Robot-assisted radical cystectomy (RARC) has been shown to have comparable oncologic efficacy compared to open radical cystectomy (ORC). We sought to compare the rates of benign strictures after RARC and ORC using a population-based data. Methods: From Surveillance, Epidemiology, and End Results (SEER)-Medicare, we identified 332 RARC and 1449 ORC performed during 2009 and 2014, using International Classification of Diseases-9th edition and Current Procedural Terminology 4th edition to compare the development of ureteroenteric strictures at 6 months, 1 year and 2 years following radical cystectomy. We defined ureteroenteric stricture as the need for procedural intervention, consistent with prior studies. Additionally, we compared the incidence of stricture diagnosis. Multivariable proportional hazards regression was performed to determine factors associated with stricture development. Results: The incidence of ureteroenteric stricture at 6 months and 12 was higher for RARC vs. ORC at 12.1% vs. 7.0% (p<0.01) and 15.0% vs. 9.5% (p=0.01), respectively. However, the RARC vs. ORC stricture incidence at 2 years did not differ significantly at 14.6% vs. 11.4% (p=0.29). Similarly, the stricture diagnosis rates were significantly lower following ORC at 6, 12, and 24 months (p<0.05). In adjusted analysis, RARC (HR 1.70, 95% CI 1.28-2.26) and pre-operative hydronephrosis (HR 1.48, 95% CI 1.15-1.91) were associated with the development of stricture. Conversely, higher hospital volume was associated with a lower risk of stricture (HR 0.43, 95% CI 0.29-0.63). Conclusions: RARC is associated with a higher rate of post-radical cystectomy stricture complication diagnosis and intervention on a population-based level that is mitigated by higher hospital volume. Technical factors are likely responsible and prospective studies are needed to assess the influence of ureteral dissection, tissue handling and perfusion, redundancy, and/or tension on the anastomosis. A significant study limitation is the inability to differentiate extracorporeal versus intracorporeal diversion with our use of administrative data.