bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reducing overuse of PSA screening in primary care practices.
Authors: Litvin Cara B 
Published: March 2019

37 Background: The United States Preventive Services Task Force and the American Urological Association both recommend against routine PSA-based screening for prostate cancer in men 70 years and older and, for men younger than 70, recommend shared-decision making to discuss the potential benefits and harms of screening before a PSA is ordered. The HIT-OVERUSE study was a 2 year group randomized study from August 2016 thru July 2018 to test a practice-based intervention to reduce overuse in primary care practices, including avoidance of routine PSA screening without shared decision-making. The purpose of this report is present the impact of this intervention on PSA screening. Methods: Twenty one primary care practices in 19 states volunteered to participate in the study. Prior to randomization, all providers received academic detailing on prostate cancer screening recommendations. Eleven practices randomized to the intervention group then received quarterly performance reports, hosted site visits for participatory planning and sent two practice representatives to a one day meeting to share ‘best practices’. The ten control practices only received performance reports. Changes in PSA testing in the past year (excluding patients with prostate cancer) were compared in control and intervention practices. Results: At the patient level, there was a significantly larger unadjusted reduction in PSA screening in men ages 40 to 69 in the past year between intervention practices (28.6 % to 19.0%) and control practices (16.5% to 12.7%) (p<0.0001). There was also a significantly larger unadjusted reduction in PSA screening in men ages 70 and older in the past year between intervention practices (25.7% to 14.7%) and control practices (21.9% to 15.6%) (p<0.0001). Adjusted changes will also be presented. Conclusions: A practice-based intervention to reduce routine PSA-screening performed without shared decision-making resulted in a greater reduction in PSA screening compared to provision of academic detailing alone. Further research could elucidate whether this type of intervention results in increased shared decision-making conversations with patients.
Comparing radical cystectomy with trimodal therapy for patients diagnosed with bladder cancer: Critical assessment of statistical methodology and interpretation of observational data.
Authors: Ray-Zack Mohamed Danny , Shan Yong , Kerr Preston , Kosarek Christopher David , Hudgins Hogan K , Jazzar Usama , Kaul Sapna , Kamat Ashish M. , Tyler Douglas S. , Swanson Todd A. , Mehta Hemalkumar B , Williams Stephen Bentley 
Published: March 2019

373 Background: Treatment guidelines for muscle-invasive bladder cancer recommend radical cystectomy. However, use of trimodal therapy has increased in recent years with conflicting survival outcomes. The aim of this study was to compare radical cystectomy and trimodal therapy in terms of survival outcomes and cost of treatment according to varying statistical methodology in order to interpret findings using observational data. Methods: Patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002-December 31, 2011 were included from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Outcomes included cancer-specific survival, overall survival, and 6-month costs. Cox proportional hazards regression, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to control for baseline differences between patients undergoing radical cystectomy vs. trimodal therapy, and to determine predictors for overall and cancer-specific survival. Results: A total of 2,963 patients were included: 728 (24.6%) who underwent trimodal therapy were compared to 2,235 (75.4%) who underwent radical cystectomy. In all adjusted analyses, patients who underwent trimodal therapy had significantly decreased cancer-specific survival (Cox regression: Hazard Ratio (HR) 1.51, 95% Confidence Interval (CI) 1.40-1.63; PSM: HR 1.55, 95% CI 1.32-1.83; IPTW: HR 1.51, 95% CI 1.40-1.63) and overall survival (Cox regression: HR 1.54, 95% CI 1.39-1.71; PSM: HR 1.49, 95% CI 1.31-1.69; IPTW: HR 1.54, 95% CI 1.39-1.71). However, median total costs over six months were significantly higher with trimodal therapy than radical cystectomy ($171,401 vs. $99,890, p<0.001). Conclusions: Trimodal therapy was associated with decreased cancer-specific and overall survival at increased costs compared to radical cystectomy. In the absence of data from randomized controlled trials, this observational study provides further evidence to suggest the superiority of radical cystectomy over trimodal therapy in patients with muscle-invasive bladder cancer.
Presurgical anemia as a predictor of relapse and survival in bladder carcinoma treated with cystectomy.
Authors: Pinto Alvaro , García Luis Eduardo , García Esther , Herradon Noelia , Espinosa Enrique 
Published: March 2019

382 Background: Bladder carcinoma is the fifth most common neoplasm in developed countries. When muscle-invasive disease is diagnosed in a localized stage, radical cystectomy is the standard treatment, with or without perioperative chemotherapy. In this retrospective study we aim to identify presurgical factors that correlate with relapse risk and survival in patients being treated with radical cystectomy without neoadjuvant chemotherapy. Methods: Patients with a history of radical cystectomy for non-metastatic muscle-invasive bladder carcinoma from 1995 to 2010 were included. They had to have an appropriate follow-up, and tissue available for further correlative studies. Demographic baseline features and therapy outcomes were collected in a retrospective fashion. Results: A total of 158 patients were included, with a median overall survival (OS) for the entire cohort of 51 months (95% IC: 17.1–84.9 months). Median relapse free survival (RFS) is 39 months (95% IC: 3.8–74.1 months). In univariate analysis, the following features were prognostic factors for RFS: ECOG performance status (0 vs ³1; 72 vs 20 months, p=0.014), hemoglobin levels (normal vs low; 144 vs 21 months, p=0.001), free surgical margins (yes vs no; 39 vs 11 months, p=0.004), lymph node status (pN0 vs pN+; 119 vs 18 months, p<0.001) and pT stage (pT2 vs pT3-4; 167 vs 20 months, p< 0.001). Other previously described factors, such as neutrophil-lymphocite ratio, thrombocytosis, creatinine clearance or the presence of hydronephrosis, were not significant in our group of patients. In the multivariate analysis, only ECOG (HR 2.32), lymph node status (HR 2.0) and hemoglobin levels (HR 1.71) were independent predictors for RFS. Conclusions: In our group of patients, apart from ECOG performance status and lymph node status, the presence of presurgical anemia could be an indicator of poorer outcomes after cystectomy. These patients should be monitored closely and maybe considered for further therapeutic procedures, such as adjuvant systemic therapy.
Assessment of the diagnostic value of microsatellite instability in the urine of bladder cancer patients.
Authors: Khaled Hussein Mustafa , Zekri Abdel-Rahman , Mohamed Mai B , Diab Fatma M , Abdellateif Mona , El Deeb Somaya Cancer , Badr Abeer M , Abdallah Sanaa O , Bahnassy Abeer Ahmed 
Published: March 2019

384 Background: Microsatellite alterations in urine sediments have proved to be a promising tool for detection of bladder cancer (BC) due to its high sensitivity and specificity. Methods: We assessed the possible prognostic and predictive values of microsatellite alterations in tissue samples and urine sediments obtained from Egyptian patients with BC, and their utility as diagnostic, prognostic and predictive value. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were assessed using 13 microsatellite markers in tumor tissue and urine sediments of 30 patients with BC. The concordance between MSI in tissue and urine samples was determined. Results: We found that MSI was more frequent than LOH (100% and 46.7%; respectively). D16S310, MBP and IFN-α showed the highest MSI frequency in urine samples (70%, 70% and 66.67%; respectively), while MBP, ACTBP2 and D9S171 (66.67%, 63.33%, and 60%; respectively) were the most frequently detected in tumor tissue. All markers correlated significantly with the pathological subtypes (more frequent in TCC) and hematuria. The concordance between tissue and urine was statistically significant for , D9S171, D16S476, FGA and ACTBP2 (P = 0.04, 0.015, 0.02 and 0.007; respectively). When we combined D16S476 and D9S171, the sensitivity, specificity, PPV and NPV reached (80.0%, 75.0%, 82.8% and 71.4%; respectively) for diagnosis of BC . Conclusions: Thus MSI in urine sediments could be a sensitive and reliable method for diagnosis of BC.
A phase II trial to evaluate pemetrexed clinical responses in relation to tumor methylthioadenosine phosphorylase (MTAP) gene status in patients with previously treated metastatic urothelial carcinoma.
Authors: Alhalabi Omar , Campbell Matthew T , Slack-Tidwell Rebecca , Siefker-Radtke Arlene O. , Shah Amishi Yogesh , Efstathiou Eleni , Wang Wei-Lien , Titus Mark Anton , Czerniak Bogdan , Zhang Miao , Guo Charles , Logothetis Christopher , Gao Jianjun 
Published: March 2019

385 Background: According to The Cancer Genome Atlas, 26.8% of bladder tumors harbor homozygous deletion of the MTAP gene, which encodes for an essential enzyme for the salvage pathway of nucleotide synthesis. Pemetrexed is a well-known anti-folate agent that inhibits the de novo pathway of nucleotide synthesis. Therefore, we hypothesized that tumors with MTAP gene loss have a synthetic lethality to pemetrexed due to loss of both essential nucleotide synthesis pathways. We proposed a study to determine pemetrexed response rate in patients with MTAP-deficient metastatic urothelial carcinoma (mUC). Methods: We carried out a single-arm, open-label, phase II clinical trial with pemetrexed in patients with mUC and MTAP loss by immunohistochemistry. This is an interim analysis of results. Each patient receives pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. Pemetrexed is continued until progression of disease (PD) and a repeat biopsy is obtained at that time. Pre- and post-treatment blood, urine and tumor samples are obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Six patients have been enrolled on this trial and all have received at least one previous treatment including a cisplatin-containing regimen in 5 (83%) patients and an immune checkpoint inhibitor in 4 (66%) patients. Of these 6 patients, 1 (17%) had complete response (CR); two (33%) had partial response (PR); 1 (17%) had stable disease; 1 (17%) was not evaluable; 1 (17%) had PD. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Only 2 of 6 patients developed grade 3 anemia. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: Our study show that in heavily pretreated MTAP deficient mUC patients, pemetrexed is still an effective and well-tolerated therapy with an objective response rate (ORR=CR+PR) of 50%, which is higher than previously reported pemetrexed activity (ORR=8-28%) as first or second line treatment for mUC. Clinical trial information: NCT02693717.
Treatment of locally advanced or metastatic urothelial carcinoma: Analysis of expert and community healthcare provider practice trends.
Authors: Rosenthal Kristen , Galsky Matt D. , Milowsky Matthew I. , Petrylak Daniel Peter , Rosenberg Jonathan E. , Obholz Kevin , Plimack Elizabeth R. 
Published: March 2019

389 Background: With new indications for immune checkpoint inhibitors (ICI), treatment (Tx) decisions for patients (pts) with locally advanced (LA) and metastatic (m) urothelial carcinoma (UC) are becoming more complex. Methods: In Jan 2018, 5 UC experts developed an online tool to provide specific Tx recommendations for 318 case variations based on key factors. Healthcare providers (HCP) enter pt information and their intended Tx to see expert Tx choices for that case. We compared intended Tx of HCPs vs expert recommendations for 388 cases entered in the tool from Feb 1-Aug 15, 2018, before the FDA label change for ICI requiring PD-L1 testing for cisplatin-ineligible pts. Pearson chi-squared and Fischer’s exact tests were used. Results: In LA UC, experts chose cisplatin-based chemotherapy (CT) for 94% of eligible pts vs 59% of HCP ( P < .0001). In pts ineligible for any platinum (Plt)-based CT, experts selected pembrolizumab for all cases vs only 10% of HCP ( P < .0001). In pts with untreated mUC, experts picked cisplatin-based CT in 93% of eligible cases vs 60% of HCP ( P < .0001) and experts chose pembrolizumab for 91% of pts ineligible for any Plt-based CT vs 22% of HCP ( P = .0001). For cisplatin-ineligible pts with either LA UC or mUC who may be able to tolerate carboplatin, there was more variability in expert and HCP Tx choices (Table) prior to the updated ICI indications. For pts who progressed after 1 or 2 lines of CT (including Plt CT), experts chose pembrolizumab for 99% of cases vs 28% of HCP ( P < .0001); 22% of HCP were uncertain of Tx. Although pembrolizumab was the preferred ICI by experts for these 2nd and 3rd line cases, 31% of HCP chose a different ICI. Conclusions: Tx patterns between experts and HCP differed significantly for UC across multiple settings, particularly with integration of ICIs into clinical practice. As treatment indications for ICI continue to evolve, HCP can benefit from an online tool with expert guidance to help navigate complex Tx choices. [Table: see text]
Long-term outcomes in elderly patients (pts) from IMvigor210: Atezolizumab (atezo) in metastatic urothelial cancer (mUC).
Authors: Balar Arjun Vasant , Dreicer Robert , Loriot Yohann , Perez-Gracia Jose Luis , Hoffman-Censits Jean H. , Petrylak Daniel Peter , Van Der Heijden Michiel Simon , Shen Xiaodong , Ding Beiying , Ramirez-Montagut Teresa , Rosenberg Jonathan E. 
Published: March 2019

394 Background: Cisplatin-based chemotherapy is currently the standard 1L treatment for mUC, but many pts are ineligible and progression is common. Atezo (anti–PD-L1) is approved for certain types of mUC, and long-term efficacy and safety have been shown (Balar, ASCO 2018). Elderly pts in particular tend to have poor outcomes and may be chemotherapy intolerant, so this analysis sought to evaluate clinical outcomes in pts aged ≥ 65 and ≥ 75 y from the Phase II IMvigor210 study. Methods: This 2-cohort, single-arm study enrolled pts ineligible for 1L cisplatin and previously platinum-treated pts. Atezo 1200 mg IV q3w was given until PD (Cohort 1) or loss of clinical benefit (Cohort 2). RECIST v1.1 ORR (independent review; primary endpoint) and DOR and OS (secondary) were evaluated in pt subgroups based on PD-L1 status and age. Results: Evaluable pts as of July 12, 2018, are shown in the Table. In Cohort 1 pts ≥ 75 y, ORR was 29% overall, CR rate was 8%, DOR was NE and median OS was 21.4 mo. In Cohort 2 pts ≥ 75 y, ORR was 23%, CR rate was 7%, mDOR was 20.9 mo and mOS was 9.2 mo. Updated safety analyses in elderly pts will be presented. Conclusions: Efficacy outcomes in IMvigor210 elderly pts with mUC, and PD-L1 subgroup analysis appear generally consistent with those in the overall population in this long-term analysis. (Cohort 1; Balar Lancet 2017; NCT02951767). (Cohort 2; Rosenberg Lancet 2016; NCT02108652). Clinical trial information: NCT02951767 and NCT02108652. [Table: see text]
Trends in checkpoint inhibitor therapy for advanced urothelial cell carcinoma (aUC) at the end of life: Insights from real-world practice.
Authors: Parikh Ravi Bharat , Galsky Matt D. , Gyawali Bishal , Riaz Fauzia , Kaufmann Tara Laura , Cohen Aaron Benjamin , Adamson Blythe J.S. , Gross Cary Philip , Meropol Neal J. , Mamtani Ronac 
Published: March 2019

395 Background: National guidelines recommend against chemotherapy use at the end of life. Five CPIs are now approved for aUC. We hypothesized that oncologists may have a lower threshold to initiate CPI in patients (pts) at the end of life, particularly among pts with poor performance status (PS), because of the perceived favorable toxicity profile of CPI. Methods: We conducted a secular trend analysis using the Flatiron Health Database, a large real-world electronic medical record-derived dataset. We used nonparametric tests of trend (p values reported as ptrend) to evaluate quarterly proportions of pts initiating CPI, chemotherapy, or no systemic therapy within 30 and 60 days of death, among 2959 pts diagnosed with aUC from 2015 to 2017. Results: 1637 pts died during follow-up and were eligible for analysis. 278 (17.0%) and 488 (29.8%) pts initiated a new line of systemic therapy in the last 30 and 60 days of life, respectively. The quarterly proportion of CPI initiators within 60 days of death increased from 1.0% to 23% during the study period ( ptrend < 0.001), with corresponding decreases in chemotherapy initiation and no systemic therapy. After CPI approval in mid-2016, CPI initiation significantly increased among pts with Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 ( ptrend = 0.02) but did not significantly change among pts with PS 0-1. Initiation of any systemic therapy at the end of life doubled (17.4% to 34.8%) over the study period, driven largely by end-of-life CPI use. Compared to chemotherapy initiators, CPI initiators had slightly worse PS (table). Conclusions: In patients with aUC, there has been a dramatic rise in CPI initiation at the end of life particularly among pts with poor PS. Existing guidelines on systemic therapy initiation near the end of life should account for the increasing use of CPI. [Table: see text]
Characterization of genomic alterations as biomarkers of immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma (mUC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian 
Published: March 2019

400 Background: ICIs have expanded therapeutic options for mUC patients (pts); however, biomarkers such as PD-L1 have not served as reliable predictors of treatment efficacy. High tumor mutation burden (TMB) has been previously described as a potential biomarker for predicting ICI response in several indications, but its utility is still being explored in mUC. Here, we compare the genomic landscapes and clinical outcomes of mUC pts following ICI therapy using an investigational solid tissue-based next-generation sequencing assay to assess TMB and identify genetic correlates of ICI response. Methods: 20 pts with mUC treated with ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated with a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also stained for PD-L1 status using the Dako 22C3 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated using RECIST 1.1 criteria. Results: Pts were grouped by overall response following ICI therapy as either responders (“R”, n = 6) or non-responders (“NR”, n = 13). Pts exhibited a wide range of TMB scores (0.7 to 30.4 mutations/Mb), with a mean TMB score of 9.60 vs. 3.87 mut/Mb in R vs NR groups, respectively; however, this difference was not statistically significant ( p = 0.284). 18 pts were evaluated for PD-L1 status, with only 2 positive samples (one in each group). Rs had significantly more mutations in histone methylation genes (KDM6A, KMT2C, and KMT2D), (67% vs 15% in NRs, p = 0.0039). FGFR3 mutations were also more frequent in R vs NR (67% vs 5%, p = 0.0339). Finally, there was a higher frequency of mutations in TP53 and BRCA1 in the NRs. Conclusions: In this mUC cohort, neither TMB nor PD-L1 correlated with response to ICI therapy. Histone modifying genes and FGFR3 mutations were more frequent in responders, whereas BRCA1 and TP53 mutations were enriched in non-responders, warranting future prospective studies to understand underlying mechanisms of ICI response and resistance in mUC.
Serial ctDNA tracking reveals clonal evolution dynamics in advanced urothelial carcinoma (UC).
Authors: Villamar Dario Martin , Price Kristin Sedgwick , Nagy Rebecca , Tagawa Scott T. , Molina Ana M. , Nanus David M. , Grivas Petros , Sonpavde Guru , Vogelzang Nicholas J. , Faltas Bishoy Morris 
Published: March 2019

401 Background: UC is characterized by extensive genomic heterogeneity. Access to genomic DNA from all metastatic lesions is infeasible. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) may recapitulate heterogeneity and offer an opportunity for continuous tracking of tumor evolution. Methods: We analyzed a cohort of advanced UC patients with serial (2 time points) ctDNA NGS using Guardant360. Restaging scans were examined to determine the relationship between ctDNA dynamics and radiologic progression. We performed whole exome sequencing (WES) of a subset of the corresponding tumors to define patterns of genomic heterogeneity. Results: NGS was performed on 214 individual ctDNA samples from 78 advanced UC patients (61 M, 17 F). A minimum of 2 serial ctDNA tests per patient (range 2-8) were collected over an average 21.5 (2-108) weeks between samples. Molecular alterations (MAs) were identified in 188 (88%) of samples with a mean of 4.3 alterations (1-31) per sample. 184 (85%) samples harbored SNVs, 30 (14%) harbored indels and 36 CNVs (17%). Most commonly mutated genes were TP53 (18%), ARID1A, NF1 (4.5% each ), EGFR (3.5%), FGFR3 (3.4%), ERBB2 and PIK3CA (3.4% each ). The most frequently amplified genes were ERRB2 and CCNE1. Serial analysis of maximum variant allele frequency (mVAF) revealed a mean 7.5-fold change between 1st and 2nd and a 6-fold change between 2nd and 3rd ctDNA samples. Interestingly, the mean rate of mVAF fold change/week was stable between serial testing time points (0.35, 0.32 p = 0.7). We observed that patients with higher initial mVAF ( > 3%) experienced a significantly larger mean fold decrease compared to patients with initial mVAF below this threshold (p = 0.008). In patients with available restaging scans timed with ctDNA testing, all patients with radiologic progression exhibited increasing mVAF (mean: 8-fold). Interestingly, ctDNA identified several clinically-significant somatic MAs not present on matching tumor WES including PIK3CA (T727R, M1043I), TP53 (Q331*, P190L), RB1 (R556*, Q257*), APC (D2527H), and BRCA2 (P2804S).WES is ongoing in more patients. Conclusions: ctDNA sequencing enables dynamic monitoring of therapy-driven clonal evolution patterns of advanced UC.