bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying factors associated with poor genitourinary cancer clinical trial accrual using a novel data extraction algorithm.
Authors: Stensland Kristian D. , Reinstatler Lael Suzanne , Moinzadeh Alireza , Galsky Matt D. 
Published: March 2019

439 Background: Poor accrual to clinical trials is the most cited barrier to efficient trial completion, yet information regarding accrual adequacy is limited. Comparisons of planned (or anticipated) accrual to actual accrual have previously been limited by siloed information. Even ClinicalTrials.gov presents only one type of accrual (actual OR anticipated) for each trial. We developed a novel approach to extract both anticipated and actual trial accrual. We apply these previously unavailable data to describe accrual adequacy and identify predictors of poor accrual. Methods: Records for all GU cancer clinical trials started since 2005 were extracted from ClinicalTrials.gov. We employed a custom Python web scraper to extract anticipated and actual accrual information and trial characteristics from the ClinicalTrials.gov archives. Logistic regression was used to identify predictors of failing to meet 50% or 85% of anticipated accrual. Results: A total of 3,976 completed or terminated genitourinary cancer trials were extracted, of which 1,322 unique trials had complete records. Only 42% of trials met their anticipated accrual goals, and 30% enrolled fewer than half of their anticipated patients (Table). Of trials reported as completed, only 54% reached their accrual goals; 17% failed to reach 50% of anticipated accrual. On logistic regression, prostate (OR 0.64, 95% CI 0.45-0.91) and testicular (OR 0.44, 95% CI 0.18-0.96) trials, as well as trials with sites within and outside the USA (OR 0.55, 95% CI 0.35-0.86) were more likely to accrue > 50% of anticipated patients. Conclusions: Genitourinary cancer clinical trials frequently fail to meet anticipated accrual goals. Whether this represents overly ambitious goals or modified endpoints after a trial opens remains uncertain. These data should be transparent and applied to the interpretation of results. Future work in this regard should be used to aid in planning future trials. [Table: see text]
Analysis of real-world PD-L1 testing in patients with urothelial carcinoma.
Authors: Krigsfeld Gabriel S , Prince Emily , Zerba Kim , Chizhevsky Vladislav , Ragheb Josette William , Novotny James , White James William 
Published: March 2019

447 Background: Programmed death-1/programmed death ligand 1 (PD-1/PD-L1) inhibitors are FDA-approved for urothelial carcinoma (UC) among other tumor types. PD-L1 immunohistochemistry (IHC) testing for UC has evolved with several diagnostic approvals. As of August 2018, the Dako PD-L1 IHC 22C3 pharmDx is a companion diagnostic, while the Dako PD-L1 IHC 28-8 pharmDx and the Ventana PD-L1 (SP263) assays are complementary diagnostics. The Ventana PD-L1 (SP142) assay has complementary status for platinum-treated patients with UC but gained companion status in July 2018 for cisplatin-ineligible patients with PD-L1-expressing UC. Here, we assess PD-L1 testing with the 22C3, 28-8, and SP142 assays on real-world UC samples. Methods: Analyses on 55,652 tumor samples from Symphony Health Solutions were performed between October 2015 and March 2018. PD-L1 results were linked to clinical characteristics using unique identifiers. PD-L1 testing on UC samples was performed at NeoGenomics Laboratories, Inc. based on the manufacturer’s protocols at the time. Results from the Dako assays were reported as % of tumor cells with PD-L1 expression. Test failure (TF) was defined as the absence of adequate sample with measurable PD-L1. Turnaround time (TAT) was defined as the time from sample receipt by the laboratory to test-report delivery. Paired 28-8 and 22C3 testing was performed on 13 samples. Results: 251 confirmed PD-L1 IHC tests (0.4% of tests conducted for the entire dataset) were performed on 223 UC samples, 98.2% of which had quantifiable PD-L1 expression. Mean TAT was 3.0 (1.0–4.2) days and the TF rate was 2.0% for all tests. The 22C3, 28-8, and SP142 assays were used in 52.2%, 9.6%, and 38.3% of tests, respectively. Paired testing with the 22C3 and 28-8 assays was highly correlated (Spearman’s r = 0.94; n = 13). Further analyses of UC PD-L1 prevalence will be presented. Conclusions: Based on the total tests conducted by this US national reference laboratory, PD-L1 testing was not commonly requested for UC during the analysis period. However, PD-L1 tests that were conducted displayed high success rates and reasonable TAT. This is the first comparison of the 22C3 and 28-8 assays on real-world UC samples, adding to the literature on PD-L1 testing concordance.
SPEAR-Bladder (Study informing treatment Pathway dEcision in bladder cAnceR): Influence of treatment sequencing on time to treatment failure and overall survival in the United States.
Authors: Doshi Gurjyot K. , Kearney Mairead , Bharmal Murtuza , Phatak Hemant , Boyd Marley , Aguilar Kathleen , Kim Ruth , Bhanegaonkar Abhijeet 
Published: March 2019

453 Background: With the introduction of immunotherapy (IO) for locally advanced or metastatic urothelial carcinoma (mUC), optimal treatment sequence should be considered. This study aimed to compare time to treatment failure (TTF) and overall survival (OS) among these patients (pts) treated with first-line (1L) systemic chemotherapy followed by second-line (2L) IO ( C-IO) vs 1L and 2L chemotherapy ( C-C) sequence within the US community oncology Network (USON). Methods: This was a retrospective study of adult locally advanced or mUC pts who initiated systemic therapy between 1/1/15 – 4/30/17 within USON and had a minimum of two-month follow-up. Descriptive analyses were performed, with Kaplan-Meier used for comparisons between pts who received C-IO vs C-C sequence. Pts considered for this analysis did not receive a third-line treatment. Regression analyses were performed to assess variables associated with TTF and OS. Results: 117 pts were included in the analysis ( C-IO n = 79, C-C n = 38). Median age (range) was 69 years (38, 90+), with 74.4% male. Baseline demographic and clinical characteristics were similar between the groups. The median (range) duration between start of 1L and start of 2L therapy was significantly longer among C-IO vs C-C pts (29.0 [4.1, 102.1] vs 20.0 [0.1, 63.1] weeks; P = 0.0047). Median TTF and OS were longer among C-IO vs C-C pts but the trends were not significant (Table). The duration between initial diagnosis and advanced disease status was associated with TTF (P = 0.0124) in univariate analysis. Conclusions: These results suggest that patients receiving C-IO demonstrated greater (>30 weeks) but statistically non-significant improvement in OS versus those receiving C-C. Considering these OS trends, future research should explore prognostic characteristics of IL chemotherapy treated pts who may benefit from an earlier switch to IO therapy. [Table: see text]
Invasive urothelial cancer (iUC) with FGFR3 hotspot mutation/fusion (FGFR3+): A molecularly and clinically distinctive entity?
Authors: Mota Jose Mauricio S. C. , Teo Min Yuen , Li Han , Balar Arjun Vasant , Milowsky Matthew I. , Funt Samuel Aaron , Lee Chung-Han , Regazzi Ashley Marie , Berger Michael F. , Solit David B. , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa 
Published: March 2019

459 Background: FGFR3+ is ubiquitous in non-invasive UC but found in ~16% of iUC. We sought to characterize the genomic landscape and response to platinum-based chemotherapy (ctx) of FGFR3+ iUC in the neoadjuvant (NAC) and metastatic (mUC) setting. Methods: Two molecularly-characterized cohorts were used for the study objective: (1) NAC-treated muscle invasive UC, incorporating consecutively sequenced standard of care UC and patients (pts) from a phase II trial (Iyer et al, JCO 2018); (2) mUC treated with platinum ctx, with FGFR3- mUC from a published work (Teo et al, CCR 2017) serving as comparator. iUC with hotspot mutations / fusions were considered FGFR3+. Clinical outcomes and frequency of altered genes were compared. Results: In the NAC cohort, 87 pts were identified (NAC response: pT0 [n = 20, 23%], <pT2 [n = 22, 25%], ≥pT2 [n = 45, 52%]). FGFR3+ (n = 11, 13%) was associated with a trend towards poor NAC response and was found in 0/20 pT0 (0%), 3/22 <pT2 (14%) and 8/45 ≥pT2 (18%) (Cochran-Armitage, p=0.06). Among ≥pT2 tumors, FGFR3+ was associated with shorter recurrence-free survival (3.7 vs 17.6 months; HR 4.8 95% CI 1.9–12.1). 49 FGFR3+ mUC pts were identified and compared to FGFR3- mUC (n = 82). FGFR3+ had a numerically higher rate of lung metastasis (42% vs 29%, p = 0.25). 1st line therapies included: platinum-based ctx (n = 27), non-platinum ctx (n = 4), immunotherapy (IO, n = 13), ctx + IO (n = 4), and FGFR inhibitor (n = 1). Platinum ctx response rate for 21/27 evaluable FGFR3+ pts was 40%. FGFR3+ mUC had similar overall survival (OS, median 25.7 vs 15.8 months, HR 0.7, 95%CI 0.4-1.2; 1-year OS: 70% vs 59%) and progression-free survival (median: 7.2 vs 7.1 months, HR 1.3, 95% CI 0.8-2.1). Frequencies of altered genes are tabulated. No differences in mutational load were seen. Conclusions: FGFR3+ iUC is a genomically distinct subset of iUC. Despite low responses to NAC ctx, FGFR3+ had similar responses, PFS, and OS in the mUC setting. [Table: see text]
Regulation of stem cell-like phenotype and response to chemotherapy in bladder cancer by beta-arrestins.
Authors: Hennig Martin Jp , Kallifatidis Georgios , Smith Diandra K , Morera Dailey S , Hupe Marie C , Kuczyk Markus A , Merseburger Axel S. , Lokeshwar Vinata B 
Published: March 2019

461 Background: Identification of molecular drivers that promote a muscle invasive phenotype and chemoresistance in bladder cancer, as well as an understanding of their mechanism of action should help in designing potential prognostic markers and effective targeted treatments for patients with advanced bladder cancer. β-arrestins (ARRBs) are classic attenuators of G-Protein coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. Methods: β-arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63; n = 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated using CRISPR-Cas9 mediated gene-knockout of ARRB1. The consequence of forced expression of ARRBs on tumor growth and response to gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. Results: ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared to normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ~ 80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity towards gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. Conclusions: β-Arrestins regulate response towards gemcitabine and are therefore potential targets and predictive markers for chemotherapy failure in bladder cancer. The present work shows for the first time that β-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer.
Let-7f microRNA expression within established bladder cancer subtypes and upregulation with recombinant interferon-alpha.
Authors: Narayan Vikram M , Lim Amy , Mokkapati Sharada , Manyam Ganiraju C. , Plote Devin , Sundi Debasish , Choi Woonyoung , Dinney Colin P.N. 
Published: March 2019

462 Background: Let7f is a microRNA (miR) that may act as a tumor suppressor in multiple human malignancies. In patients with BCG-refractory non-muscle invasive bladder cancer, detectable let7f levels in the urine of patients undergoing treatment with adenoviral vector-mediated IFNα gene therapy (clinical trial setting) were found to be prognostic of treatment response at 12 months. Here we sought to define the association of let7f with clinical bladder cancer phenotypes within The Cancer Genome Atlas (TCGA) cohort and characterize the role of let7f in preclinical models. Methods: Using miRNA sequencing data from the published TCGA 2018 bladder cohort (n = 412), let7f miR expression was characterized and stratified by molecular subtype (basal-squamous, luminal, luminal-infiltrated, luminal-papillary, and neuronal). Kaplan-Meier analyses were performed to compare survival (upper vs lower median, by let7f expression level). The murine urothelial carcinoma cell line MB49 was cultured in colonies of 105 and in vitro administrations of 100U/mL of recombinant mu-IFNα were performed with cells harvested at 0, 2, 8, 12, and 24 hours. Let7f miR expression levels were then determined by qRT-PCR. Results: Within the TCGA cohort, let7f expression levels were found to be lower in the more aggressive basal-squamous (median = 12.8), luminal-infiltrated (median = 12.9), and neuronal (median = 12.4) subtypes relative to the luminal (median = 13.2) and luminal-papillary (median = 13.3) subtypes (p < 0.001). Survival analysis demonstrated a trend towards improved survival in the high let7f expressers, but this did not reach statistical significance. In MB49 cells treated with mu-IFNα, there was a time-dependent increase in let7f miR expression suggesting that IFNα may play a role in upregulation of this potential tumor suppressor. Conclusions: Let7f miR is downregulated in more aggressive subtypes of MIBC. IFNα upregulates let7f expression in MB49 cells, and the inability to do so may comprise an escape mechanism for IFNα-treated tumors. Let7f miR may serve as a novel biomarker to identify aggressive phenotypes and treatment failures for bladder tumors treated with IFNα-based gene therapy.
Comparison of investigator-initiated and industry-initiated trials in Canada and other countries.
Authors: Wong Bryan , North Scott A. , Tran Ben , Sridhar Srikala S. 
Published: March 2019

464 Background: Investigator-initiated trials (IITs) developed by academic investigators without inherent commercial interests have contributed significantly to oncology. However, costs and regulatory complexity may negatively impact IITs. Little is published about current trends in cancer IITs. We focused on IITs in genitourinary cancers (GU IITs) in Canada and other countries and compared these to industry-initiated trials conducted over the same time period. Methods: We collected data using searches of the ClinicalTrials.gov registry for bladder, kidney, and prostate cancer trials conducted in Canada, US, and France from 2007 to 2017. IITs were defined as trials funded by individuals, universities, or organizations. We then characterized trials based on type, purpose, phase, participants, masking, assignment, and allocation. Results: Of the 498 GU trials conducted in Canada from 2007 to 2017, 201 (40%) were IITs, and 254 (51%) were industry-initiated. On average, GU IITs in Canada increased by 88% from 2007 to 2017, while industry-initiated trials increased by 30%. Although the increase of GU IITs in Canada was greater than industry-initiated trials, the growth was larger in US and France. In US, 746 (29%) of the 2537 GU cancer trials were IITs and increased by an average of 106% from 2007 to 2017, while industry-initiated trials increased by 61%. In France, 164 (41%) of the 405 GU cancer trials were IITs and increased by an average of 125% from 2007 to 2017, while industry-initiated trials increased by 83%. For GU IITs in Canada, most studies were interventional (85%) with purpose of treatment (47%). Phase 2 trials (23%) and trials with 20 to 49 participants (29%) accounted for the majority. Most trials were randomized (41%), open-label (70%), and used single group assignment (43%). GU IITs in US and France shared these same patterns in their characteristics. Conclusions: The increase in GU IITs from 2007 to 2017 was lower in Canada than US and France. In all three countries, more GU trials were industry-initiated than IITs. More emphasis must be placed on IITs in Canada through increased commitment and funding by institutions to promote development of IITs and maintain their distinctive, academically driven intentions.
Sites of metastases (mets) and their association with clinical outcomes (CO) in 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. , Kucuk Omer , Carthon Bradley Curtis , Bilen Mehmet Asim 
Published: March 2019

473 Background: Several IO agents have been approved for treatment of advanced urothelial cancer pts. We investigated the association between sites of mets and CO in urothelial cancer pts treated with IO in the real world setting. Methods: We performed a retrospective review of 67 urothelial cancer pts treated with PD-1 or PD-L1 inhibitors at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression free survival (PFS) were measured from first dose of IO to date of death or hospice referral and radiographic or clinical progression, respectively. Sites of mets were collected from radiology and clinic notes at baseline. Univariate analysis (UVA) and multivariable analysis (MVA) used Cox proportional hazard. Results: The median age was 70 and most (79.1%) were men. Pts had mets to sites such as lymph node (73.1%), bone (29.9%), liver (20.9%), lung (31.3%), and brain (1.5%). Pts with bone or liver mets had significantly shorter OS and PFS in UVA. Pts with bone mets also had significantly shorter OS and PFS in MVA (Table). The median OS of pts with bone mets was 2.2 months (12-month survival=28.0%), while those without bone mets had a median OS of 21.9 months (12-month survival=52.5%) per Kaplan-Meier estimation. The median OS of pts with liver mets was 2.2 months (12-month survival=28.6%), while those without liver mets had a median OS of 12.8 months (12-month survival=50.1%) per Kaplan-Meier estimation. Conclusions: Bone and liver mets are poor prognostic factors in urothelial cancer pts receiving IO in the real world setting. These findings should be validated in a larger study. [Table: see text]
Comparative analysis of biopsy proven lymph node positive bladder cancer patients to those with biopsy proven lymph node negative disease prior treatment.
Authors: Lim Amy , Narayan Vikram M , Seif Mohamed , Matulay Justin T. , Dinney Colin P.N. , Navai Neema 
Published: March 2019

475 Background: Many studies assessing the efficacy of chemotherapy before surgery include few clinically node positive patients or completely exclude them which make response rates in this particular subset of patients difficult to determine. Additionally, these patients are clinically node positive, making true nodal response rates unable to be determined. We report a descriptive analysis of patients with clinically node positive disease who underwent lymph node biopsy prior to any treatment and their outcomes. Methods: Data was obtained retrospectively from patients with cTanyN1-3M0 bladder cancer from 2006-2017 who underwent radical cystectomy at MD Anderson. SPSS was used for statistical analysis. Results: Among the 120 patients with cTanyN1-3M0 (median follow up 27.4 months), 40 patients underwent lymph node biopsy (LNBx). 26 (65%) patients had a positive LNBx, 14 (35%) were negative. 100% of the patients with a positive LNBx underwent primary chemotherapy. On final cystectomy, 9 (34.6%) of those patients had complete nodal response (pN0) and 9 (34.6%) had complete bladder response (pT0). 7 were pT0N0. Of the patients with a negative LNBx, 11 (78.6%) underwent neoadjuvant chemotherapy and of those patients, 7 (63.6%) were pN0 and 4 (36.4%) were pT0. Of patients that did not undergo LNBx that received primary chemotherapy (78 patients), 41 (52.6%) were pN0 and 22 (28.2%) were T0. There was no significant difference in overall or recurrence free survival between patients with a positive or negative biopsy or who did not undergo biopsy (p = .474). There was a significant improvement in overall and recurrence free survival in patients with negative nodal disease on final pathology compared to those with positive nodal disease (p < 0.001). Conclusions: Patients that had a negative LNBx were less likely to undergo primary chemotherapy. Pathologic bladder response rates correlate with nodal response rates. In cN+ patients, overall survival and recurrence free rates are not significantly different in patients without a lymph node biopsy, a positive biopsy or a negative biopsy. Finally, advanced final pathologic stage predicts worse outcomes.
Health-Related Quality of Life (HRQOL) reporting in phase III randomized controlled trials (RCTs) of metastatic prostate adenocarcinoma (mPCa) and urothelial carcinoma (mUC).
Authors: Jiang Di Maria , Brundage Michael Donald , Sweeney Christopher , Fizazi Karim , Bellmunt Joaquim , Vaughn David J. , Powles Thomas , Perlis Nathan , Kulkarni Girish S. , Sridhar Srikala S. 
Published: March 2019

478 Background: HRQOL outcomes are increasingly used to guide patient-centered care and health policy decisions, especially when treatment has a limited impact on survival. Our aim was to systematically evaluate the quality of HRQOL reporting in phase III RCTs of mPCa and mUC. Methods: A systematic literature review identified phase III RCTs evaluating palliative systemic therapies for castrate sensitive or castrate resistant mPCa (excluding androgen-deprivation therapy) and mUC, published in English between 1985 and 2018. Supplementary material and companion publications on HRQOL were also reviewed. RCTs reporting HRQOL outcomes were scored by the Minimum Standard Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials (range 0-11). Results: Of 44 RCTs in mPCa, 25 (56.8%) reported HRQOL outcomes. BPI-SF or BPI (14 RCTs) and McGill-Melzack pain questionnaire (6 RCTs) were the most commonly used generic instruments, whereas FACT-P (16 trials), validated in advanced PCa, was the most commonly used disease-specific instrument. Average score of HRQOL reporting in mPCa was 6.7. Of 21 RCTs in mUC, 7 (33.3%) reported HRQOL. EORTC QLQ-C30 (6 RCTs) was the most commonly used generic instrument. Only 1 trial used a disease-specific instrument, FACT-BL, which lacks validation in mUC. Average score in mUC was 6.6. Conclusions: Robust HRQOL data from phase III RCTs in mPCa and mUC remain limited, and most HRQOL reports had methodologic shortcomings. Although the disease-specific FACT-P questionnaire being used is validated in advanced PCa, mUC RCTs have yet to use a culturally validated instrument to assess HRQOL. Quality of HRQOL reporting has improved over time but needs to be better harmonized across trials. [Table: see text]