bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.