bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of circulating tumor DNA (ctDNA) assessment with tissue-based comprehensive genomic profiling (CGP) in metastatic urothelial cancer (mUC).
Authors: McGregor Bradley Alexander , Chung Jon , Bergerot Paulo Gustavo , Forcier Brady , Grivas Petros , Choueiri Toni K. , Ross Jeffrey S. , Ali Siraj Mahamed , Stephens Philip J. , Miller Vincent A. , Gregg Jeffrey P. , MacVicar Gary R. , Bauer Todd Michael , Pal Sumanta K. 
Published: February 2018

453 Background: Emerging data suggest a role for targeted therapy in patients (pts) with mUC whose tumors contain actionable genomic alterations (GA). Liquid biopsy of ctDNA from blood provides an attractive alternative for CGP in pts in whom tissue-based testing is not feasible. Methods: Hybrid capture-based genomic profiling was performed using FoundationACT assay in a CLIA-certified, CAP-accredited, NY State-approved laboratory. Cell free DNA was extracted from plasma using 20 ml whole blood and underwent CGP of 62 genes. Sequencing was performed to a median unique coverage of 6756× using the Illumina HiSeq 2500/4000 platform. Barcode-based error correction enabled analysis of GA at low allele frequency (AF), including base substitutions and short in/dels (AF≥0.1% for both), rearrangements, and copy number amplification. For several pts, non-temporally matched tissue-based CGP data was available. Comparisons to other CGP datasets of UC ctDNA and tissue were performed. Results: 66 pts with median age 68 (range 29-86) underwent ctDNA assessment as clinical test. There was evidence for ctDNA in 56 pts (85%), and ≥1 GA was noted in 48 pts (73%). The estimated median ctDNA fraction in plasma was 1.9%. In cases with detectable ctDNA, the most frequently altered genes were TP53 (68%), TERT-promoter (38%), PIK3CA (13%), FGFR3 (13%), KRAS (11%), NF1 (6%), ERBB2 (6%). Observed GA frequencies were comparable to prior studies of ctDNA and tissue. Both tissue and ctDNA-based CGP data with clinical correlation was available for several pts. A pt with FGFR3 GA in baseline tumor tissue had disappearance of FGFR3 GA and detection of new TP53 GA in ctDNA after targeted treatment with FGFR3 inhibitor. In a pt with ERBB2 and TP53 GAs in baseline tumor tissue, ctDNA at time of resistance to cisplatin-based therapy showed persistence of ERBB2 and TP53 GAs and new NF1 GA. Conclusions: Most pts with mUC had detectable ctDNA, and frequencies were comparable to prior data sets Detection of potentially targetable GA support further clinical utility assessment. Concordance between tissue and ctDNA in temporally matched samples with clinical annotation warrants further investigation.
Impact of neoadjuvant chemotherapy on pathologic outcomes in patients with upper tract urothelial carcinoma undergoing extirpative surgery.
Authors: Almassi Nima , Gao Tianming , Lee Byron , Stein Robert , Haber Georges-Pascal , Ornstein Moshe Chaim , Rini Brian I. , Gilligan Timothy D. , Garcia Jorge A. , Stephenson Andrew J. , Grivas Petros 
Published: February 2018

457 Background: Neoadjuvant chemotherapy (NAC) is infrequently administered to patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy or segmental ureterectomy and its impact on pathologic outcomes unclear. We examine pathologic outcomes in patients with UTUC receiving NAC before extirpative surgery using a population-based cancer registry. Methods: Patients who underwent extirpative surgery for UTUC from 2006-2014 were identified from the National Cancer Database. Among patients with available clinicopathologic data, the incidence of pathologic down-staging, defined as a lesser pathologic compared to clinical stage, was compared between patients who did and did not receive NAC. A multivariable model was developed to identify predictors of pathologic down-staging. Results: 7,244 patients were identified with non-metastatic UTUC who underwent extirpative surgery in the study period. 260 patients (3.6%) received NAC, with the use of NAC increasing over time from 2.0% patients in 2006 to 7.1% of patients in 2014 (linear trend p < 0.001). Clinical and pathologic staging data were available for 119 and 2904 patients who did and did not receive NAC, respectively. Thirty patients (25.2%) who received NAC experienced pathologic down-staging, compared to 52 patients (1.8%) who did not receive NAC (p < 0.0001). On multivariable analysis, NAC was associated with a higher likelihood of pathologic down-staging (OR 10.2, 95% CI 5.4-19.3). Additional predictors of pathologic down-staging include a higher clinical T stage (p = 0.001) and African-American race (OR 2.7, 95% CI 1.1-6.6). Compared to renal pelvis UTUC, ureteral UTUC was associated with a similar likelihood of pathologic down-staging (OR 1.5, 95% CI 0.9-2.5). Conclusions: NAC is infrequently used among patients with UTUC undergoing extirpative surgery. A higher incidence of pathologic down-staging was observed among patients receiving NAC. These findings suggest clinical benefit of NAC with respect to pathologic outcomes in patients with UTUC and may help guide selection of patients for NAC prior to radical surgery until data from prospective studies becomes available.
Novel transgenic knockout model of basal-squamous bladder cancer.
Authors: Osei Amponsa Vasty , Zheng Zongyu , Walter Vonn , Warrick Joshua , Mendelsohn Cathy , Kaestner Klaus , Wu Xue-Ru , Raman Jay , DeGraff David 
Published: February 2018

459 Background: The recent description of the highly aggressive Basal-Squamous molecular subtype of bladder cancer (BLCa) requires the development of new in vivo models for the study of this clinical entity. Although loss of the transcription factor Forkhead box A1 ( FOXA1) is significantly associated with the Basal-Squamous subtype, cooperating genetic alterations are unknown. Herein, we identify genetic alterations that potentially cooperate with FOXA1 loss to drive tumorigenesis and/or the Basal-Squamous phenotype and develop a novel transgenic model for the study of Basal-Squamous BLCa. Methods: We interrogated The Cancer Genome Atlas (TCGA) BLCa study to identify common genetic alterations associated with FOXA1 copy number (CN) loss. Based on our results, we utilized a bladder-specific Cre-LoxP ( Uroplakin II-Cre) to constitutively knock-out (KO) Foxa1 and/or Pten in mouse urothelium. Two cohorts of mice were aged for 6 and 12 months, and a third cohort was exposed to the bladder-specific carcinogen N-butyl-(4-hydroxybutyl)-nitrosamine (BBN; 0.05%) for 12 weeks. Following all experiments, the bladder tissue was isolated and characterized. Results: The TCGA data revealed that combined CN loss of both FOXA1 and PTEN occurs in 17% of MI BLCa patients. At 6 months of age, our mice developed urothelial hyperplasia, whereas at 12 months of age, double KO ( Foxa1-/-/Pten-/-) mice developed carcinoma in situ (CIS) with SqD, enriched for basal (Krt5/6 and 14) and reduced in luminal (Gata3 and Pparγ) markers. Increased tumor stage was significantly associated with combined KO of at least one allele of Foxa1 and Pten following BBN exposure. Moreover, upregulation of apoptosis related genes was observed by RNA-sequencing data. Conclusions: In advanced BLCa, CN loss of FOXA1 and PTEN is common. Genetic ablation of Foxa1 and Pten results in CIS with SqD and a pathologic profile consistent with the Basal-Squamous subtype and accelerated tumor onset following carcinogen exposure. Therefore, we describe the development of a novel model for the study of Basal-Squamous BLCa potentially useful for preclinical studies.
Minimizing prostate cancer admissions via enhanced outpatient care: A model for savings.
Authors: Parikh Anish , Sanderson Mark , Isola Luis M. , Ennis Ronald D. 
Published: February 2018

46 Background: Hospitalization is a major contributor to cost in oncology. Minimizing avoidable admissions can lead to substantial savings. Methods: We studied Medicare claims data from 160 admissions for prostate cancer (PCa) patients from 1/2012 to 5/2015. Admissions with the lowest 50th percentile of charges were assessed for being potentially avoidable by 2 independent chart reviews; remaining admissions were assumed to be unavoidable due to medical complexity. Common admitting diagnoses were targeted by theoretical care pathways designed to minimize avoidable admissions via expedited outpatient follow-up. We compared the cost of the avoidable admissions to that of implementing 3 such pathways then estimated the financial impact. Results: Total cost for all 160 admissions was $1,979,200. 25% of these admissions, accounting for $494,800, were deemed potentially avoidable. Our model exchanged each of these admissions for a routine clinic visit which led to an estimated $464,800 in savings, or a 23% improvement in total cost. The most common admitting diagnoses were fever (18%), pain (12%), and dehydration (8%). On review, 3/9 fever admissions in this set were deemed avoidable with 1 extra clinic visit, 3 with 3 visits, and 3 were unavoidable, yielding a 53% reduction in cost for this diagnosis. Similar analyses led to cost reductions of 75% and 66% for pain and dehydration admissions, respectively. Combining just these 3 theoretical interventions led to an estimated savings of $146,955, or a 7.4% improvement in total cost. Conclusions: A sizable portion of PCa admissions can be avoided, with ample savings, if a system is in place to provide the additional care that often exceeds the capabilities of a busy practice. [Table: see text]
Overall survival and treatment patterns among real-world patients with locally advanced or metastatic urothelial carcinoma treated with first-line therapy.
Authors: Simeone Jason C , Nordstrom Beth L , Patel Ketan , Klein Alyssa B , Horne Laura 
Published: February 2018

464 Background: Although platinum-based chemotherapy has been the standard of care for the treatment of locally advanced or metastatic urothelial carcinoma (UC), overall survival (OS) remains poor. Real world data on the treatment patterns for UC and effectiveness of these treatments are limited. Methods: Patients with locally advanced or metastatic UC who received first line therapy were identified from the Flatiron Oncology electronic medical record database from 2011–2016; patients who previously received immunotherapy treatment were excluded. Treatment characteristics included the most frequently administered first-line regimens in the study cohort and the time from advanced/metastatic diagnosis to start of first-line therapy. Median OS from the start of first-line therapy was calculated using Kaplan-Meier curves and 95% confidence intervals (CI) are presented. Results: Of 1,811 included patients who met study inclusion and exclusion criteria, the mean age was 70.4 ± 9.5 years, and 73.2% were male. Fewer than 3% of patients were tested for PD-L1 during follow-up. Platinum-based chemotherapy was the most commonly prescribed first-line treatment and immunotherapy was used in 1.3% of first-line regimens (Table 1); patients received a median of one treatment line during follow-up. The median OS was 12.7 months (95% CI: 11.8–13.5) from initiation of first-line therapy. Conclusions: Overall survival among locally advanced/metastatic UC patients who received first-line therapy in a real-world setting was approximately one year. As immunotherapy treatment for UC becomes more common, the impact on OS in the real world setting remains to be seen. [Table: see text]
FGFR3-TACC3 fusion in bladder cancer: Enrichment in the young, never-smokers, and Asians.
Authors: Nassar Amin , Lundgren Kevin , Pomerantz Mark , Van Allen Eliezer Mendel , Choudhury Atish Dipankar , Harshman Lauren Christine , Preston Mark A. , Mouw Kent William , Wei Xiao X. , McGregor Bradley A , Choueiri Toni K. , Bellmunt Joaquim , Kwiatkowski David J. , Sonpavde Guru 
Published: February 2018

465 Background: Bladder cancer patients (pts) are typically elderly with median age ~70 years. We hypothesized that younger pts (≤age 50) with muscle-invasive bladder cancer (MIBC) have distinct molecular features, including potential driver mutations that could serve as therapeutic targets. Methods: We used the MIBC TCGA cohort (n = 412, Cell 2017) analyzed by whole exome sequencing as a discovery cohort, and then confirmed observations using 356 pts with MIBC and high grade (HG) non-MIBC analyzed at Dana Farber Cancer Institute (DFCI) by the Oncopanel assay. Oncopanel assesses 447 somatic cancer genes and 191 regions across 60 genes for rearrangement detection by massively parallel sequencing. We examined associations between age (≤50, 51-65, and > 65) and molecular features, using the χ2 test for discrete data, and the Wilcoxon Rank Sum Test for quantitative data. Nominal p values were obtained, and the FDR correction was employed to obtain q values. Results: The following DNA alterations were significantly enriched in the TCGA in ≤50 vs 51-65 vs > 65 age groups respectively: focal deletion in CREBBP (3/25 [12%] vs 2/137 [1.5%] vs 1/250 [0.4%], p < 0.0001, q = 0.0126); microRNA Cluster III (13/25 [52%] vs 53/137 [38.7%] vs 55/250 [22%], p = 0.0005, q = 0.0252); fusion in FGFR3-TACC3 (3/25 [12%] vs 2/137 [1.5%] vs 5/250 [2%], p = 0.0055, q = 0.1386). Given that FGFR3-TACC3 fusions are potential therapeutic targets, we examined the association between FGFR3-TACC3 fusions and clinical features in a pooled analysis combining the TCGA and DFCI cohorts totaling 768 pts. FGFR3-TACC3 fusions were enriched in: ≤50 age group vs 51-65 vs > 65 (4/33 [12.1%] vs 7/232 [3%] vs 6/503 [1.2%] respectively, p = 0.0001). Fusions were also significantly more common in Asians vs. Blacks vs. Whites (6/47 [12.8%] vs 1/28 [3.6%] vs 10/666 [1.5%] respectively, p < 0.0001) and in never-smokers vs. ever smokers (12/194 [6.2%] vs 5/545 [0.9%] respectively, p < 0.0001). Conclusions: FGFR3-TACC3 fusion, a known potentially actionable genomic alteration in MIBC, is significantly enriched in young pts, never-smokers and those of Asian ethnicity. Clinical testing to detect FGFR3-TACC3 fusion should be prioritized for MIBC and HG-non-MIBC pts meeting these criteria.
Ten year treatment outcomes of radical prostatectomy vs external beam radiation therapy vs. brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Goy Barry W. , Soper Margaret S. , Burchette Raoul J. , Chang Tangel C. , Cosmatos Harry A. 
Published: February 2018

47 Background: To compare 10-year treatment outcomes of RP (radical prostatectomy) vs EBRT (external beam radiation therapy) vs BT (brachytherapy) for patients with IRPC (intermediate risk prostate cancer). Methods: A retrospective analysis using propensity score matching was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007. 819 underwent RP, 574 underwent EBRT to a median dose of 75.3 Gray, and 110 underwent BT using iodine-125. Biochemical failure was defined by the AUA (American Urological Association) definition of PSA (prostate specific antigen) failure for RP patients, and the ASTRO-Phoenix definition (American Society of Therapeutic Radiology and Oncology) for the EBRT and BT patients. Results: Median follow up was 10 years for RP, 9.6 for EBRT, and 9.8 for BT (range 1-13.4 years). With RP 76.3% had Gleason score 7 vs 72.8% for EBRT vs 57.3% for BT, p = 0.0001. Median initial PSA was 7.4 for RP, 9.4 for EBRT, and 8.3 for BT, p < 0.0001. Neoadjuvant androgen deprivation therapy was given in 58.9% of EBRT patients vs 12.7% of BT vs 0.6% for RP, p < 0.0001. Only 14% of BT received supplemental external radiation. The 10-year FFBF (freedom from biochemical failure) was 82.0% for BT vs 58.0% for RP vs 58.8% for EBRT, p < 0.0001. Subset analysis of unfavorable IRPC patients showed a 10 year FFBF of 81.6% for BT vs 55.8% for RP vs 51.0% for EBRT, p < 0.0001. The 10-year freedom from salvage therapy was 89.5% for BT vs 64.0% for RP vs 73.4% for EBRT, p < 0.0001. There were no significant differences in distant metastases-free survival, prostate cancer-specific survival, or overall survival after adjusting for age. Multivariate analysis between pairwise groups with BT balanced by stabilized inverse probability of treatment weights showed that BT remained an independent predictor for improved FFBF, p = 0.049 for BT vs EBRT, and p < 0.0001 for BT vs RP. Conclusions: Brachytherapy using iodine-125 is a reasonable treatment option for IRPC patients. Although BT showed improved FFBF after propensity score matching, this did not impact overall survival.
Perioperative hypogonadism in men undergoing radical cystoprostatectomy for bladder cancer.
Authors: Smelser Woodson , Lee Eugene , Nangia Ajay , Glavin Katherine , Holzbeierlein Jeffrey M. 
Published: February 2018

470 Background: Radical cystectomy (RC) is associated with significant morbidity, and loss of body weight is a common after RC, even in patients without significant nutritional deficiencies. Prior studies have demonstrated a high prevalence of hypogonadism (HG) in men with cancer and who undergo anesthesia/major surgery. The suppression of testosterone persists up to seven days following surgery. We hypothesize that hypogonadism is prevalent in male patients undergoing RC for bladder cancer (BC), and that it persists in the post-operative period. Methods: We implemented a prospective, IRB-approved trial (Clinical trials.gov # NCT03063125) to prospectively enroll 25 men with no prior history of treatment for HG or other hormonal disorders with a new diagnosis of non-metastatic bladder cancer undergoing RC. Pre-operative total, free testosterone and luteinizing hormone (LH) were obtained. These labs were then repeated on post-operative days 2, 3, 30, and 90. The threshold for normal total testosterone was defined as > 250 ng/dl. Demographic data were recorded. Results: Between March and September 2017, 9 patients have been enrolled into the study. Mean patient age is 68.5 years (52-85). The mean pre-operative total testosterone was 247 ng/dl (range 50-496 ng/dl) and 6/9 (66.7%) patients had HG. Two patients had abnormal pre-operative LH levels (range 21-57 mIU/L). Testosterone decreased by a mean of 99 ng/dl between pre-op assessment and post-operative day 2 [95% CI 66.2, 131.8]; all 6 men who initially had HG remained below 250 ng/dl. Two men moved from eugonadal (347 ng/dl, 316 ng/dl) to hypogonadal (213 ng/dl,192 ng/dl, respectively) by post-operative day 2. At 30 days post-op, the mean T level was 206 ng/dl. No patients had returned to levels at or above their pre-operative baseline and 8/9 (88.9%) had HG (range 40-356 ng/dl). Conclusions: Hypogonadism is prevalent in men undergoing RC; our trial demonstrates a pre- and 30 day post-operative prevalence of 66.7% and 88.9%%. Furthermore, HG persisted beyond the immediate post-operative period. Treatment of peri-operative HG with correction to a eugonadal state may represent a therapeutic intervention to reduce the morbidity associated with radical cystectomy. Clinical trial information: NCT03063125.
Cost-effectiveness of pembrolizumab in second-line advanced bladder cancer.
Authors: Sarfaty Michal , Hall Peter , Chan Kelvin K. , Virik Kiran , Leshno Moshe , Gordon Noa , Moore Assaf , Neiman Victoria , Rosenbaum Eli , Goldstein Daniel A. 
Published: February 2018

472 Background: Recently, immune-modulating drugs have been introduced to the second line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared to chemotherapy in this setting based on the Keynote-045 study. The high cost of immunotherapy necessitates an assessment of its value by considering both efficacy and cost. The objective of this study is to estimate the cost-effectiveness of pembrolizumab for the second-line treatment of advanced bladder cancer from the perspective of payers in multiple countries. Methods: We developed a Markov model to compare the costs and effectiveness of pembrolizumab with those of chemotherapy in the second-line treatment of advanced bladder cancer. Health outcomes were measured in life-years (LYs) and quality-adjusted life-years (QALYs). Drug costs were acquired for the following countries: U.S., U.K., Canada and Australia. Model robustness was addressed in univariate and probabilistic sensitivity analyses. Results: Pembrolizumab generated a gain of 0.36 QALYs compared to chemotherapy. Our analysis established the following incremental cost-effectiveness ratios (ICERs) for pembrolizumab versus chemotherapy in second-line advanced bladder cancer treatment - U.S. $122,557/QALY, U.K. $91,995/QALY, Canada $93,648/QALY, and Australia $99,966/QALY. The willingness-to-pay (WTP) thresholds per QALY are considered to be around 100,000-150,000 US dollars for the U.S., 20,000-50,000 pounds for the U.K. [25,000-65,000 US $], 20,000-100,000 CAD for Canada [16,000-80,000 US $] and 40,000-75,000 AUD for Australia [32,000-60,000 US $]. Conclusions: Cost-effectiveness and WTP thresholds vary between countries. Compared to the other countries examined, U.S. drug prices were found to be highest, leading to the highest ICER. With standard willingness-to-pay thresholds, pembrolizumab may be considered cost-effective in the U.S., but not in the other countries examined.
The DEAL trial: A diet and exercise intervention in (pre)-diabetics during treatment for non-muscle invasive bladder cancer.
Authors: Smelser Woodson , Glazyrine Vassili , Barnes Brian , Stanley Abigail , Bechtel Misty , Michel Carrie , Holzbeierlein Jeffrey M. , Hamilton-Reeves Jill , Lee Eugene 
Published: February 2018

473 Background: Patients with diabetes are at greater risk for bladder cancer (BC) as well as disease recurrence and progression. Even after controlling for clinical and pathologic risk factors, DM confers a 2x greater risk of recurrence and 9x greater risk of progression. We hypothesize that utilizing a carbohydrate restricted (CR) diet ( < 130 grams/day) to decrease the bioavailability of glucose in patients with DM and BC, a “Warburg-like” tumor, has potential therapeutic benefit. We designed a study to assess the feasibility of a CR diet in patients with (pre)diabetes and non-muscle invasive bladder cancer receiving BCG therapy. Methods: This is a pilot study of 5 (pre)diabetic patients (defined as HgbA1c > 5.7) with NMIBC receiving BCG and maintenance. A CR diet ( < 130 g/day) was supplied for the first 12 weeks through a meal delivery service. Patients received weekly coaching with a nutritionist for 6 weeks during induction BCG and at the 3 month surveillance cystoscopy with dietary and activity goals implemented. Patients had laboratory evaluation at baseline and at 3 month intervals. Patients tracked their diet. Two (1 weekday, 1 weekend day) unannounced 24 hour diet recalls were obtained to monitor compliance. Dietary compliance was defined as < 130 grams/day of carbohydrate intake. Results: Between 09/2016 and 05/2017, 5 patients were enrolled. Mean age was 66.2 years (Range 59-74). Three patients had diabetes and two patients had pre-diabetes. Two patients had CIS, 1 patient had high-grade Ta, and 2 patients had high-grade T1 disease. Mean baseline hemoglobin A1c was 7.6% (Range 5.9-11.8). Mean bodyweight and BMI were 92 kg (Range 66-105) and 28.2 (Range 23.1- 31.3) respectively. Regarding compliance, 4/5 (80%) patients completed dietary logs and weekly labs. Three patients (60%) achieved their goal of < 130 grams carbohydrates/day on 24-hour dietary recall. Average 3-month HbA1c improved from 7.6% to 6.6% (Range 5.6-7.9). Conclusions: Eighty percent of patients completed dietary logs for the first three months of the trial; 60% achieved compliance with the CR diet. These data demonstrate the feasibility of a dietary intervention utilizing CR in patients with high-grade NMIBC undergoing BCG. Clinical trial information: NCT02716623.