bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival outcomes and costs of trimodal therapy compared with radical cystectomy among patients diagnosed with localized muscle-invasive bladder cancer.
Authors: Williams Stephen Bentley , Shan Yong , Jazzar Usama , Mehta Hemalkumar B , Baillargeon Jacques G. , Huo Jinhai (Stephen) , Orihuela Eduardo , Tyler Douglas S. , Swanson Todd A. , Kamat Ashish M. 
Published: February 2018

421 Background: Radical cystectomy is the guideline-recommended treatment for muscle-invasive bladder cancer. Recently there has been a resurgence in trimodal therapy with limited data on comparative outcomes, and especially attributable costs. Methods: A total of 3,200 patients aged 66 years or older diagnosed with clinical stage T2-4a bladder cancer from January 1, 2002- December 31, 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data were analyzed. Cox regression analysis and propensity score matching methods were used to determine predictors for overall and cancer-specific survival. Results: A total of 3,200 patients met inclusion criteria. After propensity score matching, 687 patients underwent trimodal therapy and 687 patients underwent radical cystectomy. Patients who underwent trimodal therapy had significantly decreased overall (Hazard Ratio (HR) 1.49, 95% Confidence Interval (CI), 1.31-1.69, p < 0.001) and cancer-specific (HR 1.55, 95% CI 1.32-1.83, p < 0.001) survival, respectively. While there was no difference in costs at 30 days, median total costs were significantly higher with trimodal therapy than radical cystectomy at 90-d ($63,355 vs. $73,420, p < 0.001) and 180-d ($98,005 vs. $164,720, p < 0.001), respectively. Extrapolating these figures to the total US population results in excess spending of $179 million for trimodal therapy compared to less costly radical cystectomy for patients diagnosed in 2011. Conclusions: Trimodal therapy was associated with significantly decreased overall and cancer-specific survival resulting in excess national spending of $179 million in 2011 compared with radical cystectomy. These findings have important health policy implications regarding appropriate use of high-value based care among patients who are candidates for either treatment.
Novel small-molecule RORγ agonist immuno-oncology agent LYC-55716: Tumor selection and evaluation of renal cell and bladder cancer for inclusion in phase 2a expansion.
Authors: Hu Xiao , Liu Xikui , Li Hongxiu , Zawidzka Elizabeth , Weems Garry Alan , Gao Yilin , Fox Brian , Wilkins H. Jeffrey , Carter Laura 
Published: February 2018

424 Background: The master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ) controls Type 17 effector T cell differentiation and function. Synthetic RORγ agonists modulate gene expression to enhance immune effector functions and decrease regulatory T cell (Treg) development and expression of checkpoint pathways. RORγ agonists have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics analyses were performed to evaluate renal cell carcinoma (RCC) and bladder cancer (BC) for inclusion in a Phase 2a expansion trial of the investigational RORγ agonist LYC-55716 (NCT02929862). Methods: A gene signature was identified through transcriptional profiling of murine and human T cells treated ± RORγ agonists. Bioinformatics analyses were then conducted using data on RCC and BC patients from The Cancer Genome Atlas (TCGA) to determine (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, biomarkers for endogenous RORγ ligands, and correlations with patient survival rates; and (c) tumor microenvironment (TME) immune profiles. Results: Expression: RNA sequencing analysis identified RORγ+ cells in a significant fraction of RCC and BC samples. RORγ-inducing cytokines IL6, IL23a, and IL1b as well as other genes that support Type 17 differentiation were highly expressed in RCC and BC. Biology: Low expression of sterol efflux genes in RCC and BC tumors suggested low levels of endogenous RORγ ligands in the TME. Importantly, analysis revealed a positive correlation between patient survival and expression of RORγ (or the RORγ signature gene IL17A) for RCC. Immune profile: Analysis of RCC and BC tumors indicated high infiltration of CD3+, CD4+, and CD8+ T cells and high mutation burden, which are associated with immunotherapy efficacy. Conclusions: Translational and bioinformatics studies of RORγ expression, biology, and tumor immune profiles support the inclusion of RCC and BC patients in an ongoing Phase 2a expansion trial of LYC-55716.
Impact of number of cycles of platinum-based first-line chemotherapy for advanced urothelial carcinoma.
Authors: Necchi Andrea , Mariani Luigi , Lo Vullo Salvatore , Raggi Daniele , Giannatempo Patrizia , Bamias Aristotelis , Crabb Simon J. , Bellmunt Joaquim , Yu Evan Y. , Niegisch Guenter , Vaishampayan Ulka N. , Theodore Christine , Berthold Dominik R. , Srinivas Sandy , Sridhar Srikala S. , Plimack Elizabeth R. , Rosenberg Jonathan E. , Powles Thomas , Galsky Matthew , Sonpavde Guru 
Published: February 2018

426 Background: 6 cycles of platinum-based chemotherapy (CT) are conventionally targeted to treat locally advanced unresectable or metastatic urothelial carcinoma (UC). However, cisplatin is associated with significant cumulative toxicities, which render it challenging to deliver 6 cycles. Since this issue has not been investigated prospectively, we conducted a retrospective analysis. Methods: The Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) database was used to conduct a retrospective analysis. The association of the number of cycles of platinum-based first-line CT with overall survival (OS) was investigated by a Cox regression utilizing multivariate analysis after controlling for previously recognized prognostic factors used in a nomogram ( Eur Urol, 2017). The primary analysis was a comparison of < 6 cycles vs. ≥6 cycles. Six-month landmark analysis was applied throughout, accounting for OS events. Additionally, we excluded patients (pts) receiving < 3 or > 9 cycles to reduce confounding due to early removal for toxicities, progression and patient decision and increased number of cycles due to response and pt-related factors. Results: Of 1020 pts available from RISC, 472 (cisplatin = 338, carboplatin = 134) were evaluable for the landmark analysis with 281 events. A total of 157 pts received 3-5 cycles (median 4) and 315 received 6-9 cycles (median 6). There was no significant difference between 3-5 vs. 6-9 cycles of platinum-based chemotherapy (HR 1.02, 95%CI: 0.77-1.33, p = 0.91). No significant interactions were observed with type of platinum (p = 0.09) and “completed planned CT” (p = 0.56). Comparison of 4 vs. 6 cycles (p = 0.57) and < 6 vs 6 vs 7-9 (p = 0.9) also yielded no significant differences for association with OS. No differential association was observed with survival for 3-5 vs. 6-9 cycles when examining by nomogram-defined risk group tertiles. Limitations of a hypothesis-generating retrospective analysis apply. Conclusions: 4 cycles of platinum based first-line CT appear adequate to treat advanced UC. The omission of excessive cycles will avoid unnecessary toxicities and facilitate better transition to second-line and switch maintenance therapy.
Effect of detecting asymptomatic recurrence after radical cystectomy on prognosis in patients with muscle invasive bladder cancer.
Authors: Hatakeyama Shingo , Kusaka Ayumu , Kodama Hirotake , Tokui Noriko , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2018

428 Background: The prognostic benefit of oncological follow-up to detect asymptomatic recurrence after radical cystectomy (RC) remains unclear. We aimed to assess whether routine follow-up to detect asymptomatic recurrence after RC improves patient survival. Methods: We retrospectively analyzed 581 RC cases for muscle invasive bladder cancer at four hospitals between May 1996 and February 2017. All patients had regular follow-up examinations with urine cytology, blood biochemical tests, and computed tomography after RC. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of recurrence (asymptomatic group vs. symptomatic group) was estimated using the Kaplan–Meier method with the log–rank test. Cox proportional hazards regression analysis via inverse probability of treatment weighting (IPTW) was used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: Of the 581 patients, 175 experienced relapse. Among those, 12 without adequate data were excluded. Of the remaining 163 patients, 76 (47%) were asymptomatic and 87 (53%) were symptomatic at the time of diagnosis. The most common recurrence site and symptom were lymph nodes (47%) and pain (53%), respectively. Time of overall survival after RC and from recurrence to death were significantly longer in the asymptomatic group than symptomatic group. A multivariate Cox regression analysis using IPTW showed that in the patients with symptomatic recurrence was an independent risk factor for overall survival after RC and survival from recurrence to death. Conclusions: Routine oncological follow-up for detection of asymptomatic recurrence contributes to a better prognosis after RC.
Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: A multicenter study.
Authors: Hatakeyama Shingo , Kubota Yuka , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2018

429 Background: The clinical impact of neoadjuvant chemotherapy (NAC) on oncological outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC) remains unclear. We investigated the oncological outcomes of platinum-based NAC for locally advanced UTUC. Methods: A total of 426 patients who underwent radical nephroureterectomy at five medical centers between January 1995 and April 2017 were examined retrospectively. Of the 426 patients, 234 were treated for a high-risk disease (stages cT3–4 or locally advanced [cN+] disease) with or without NAC. NAC regimens were selected based on eligibility of cisplatin. We retrospectively evaluated post-therapy pathological downstaging, lymphovascular invasion, and prognosis stratified by NAC use. Multivariate Cox regression analysis was performed for independent factors for prognosis. Results: Of 234 patients, 101 received NAC (NAC group) and 133 did not (Control [Ctrl] group). The regimens in the NAC group included gemcitabine and carboplatin (75%), and gemcitabine and cisplatin (21%). Pathological downstagings of the primary tumor and lymphovascular invasion were significantly improved in the NAC than in the Ctrl groups. NAC for locally advanced UTUC significantly prolonged recurrence-free and cancer-specific survival. Multivariate Cox regression analysis using an inverse probability of treatment weighted (IPTW) method showed that NAC was selected as an independent predictor for prolonged recurrence-free and cancer-specific survival. However, the influence of NAC on overall survival was not statistically significant. Conclusions: Platinum-based NAC for locally advanced UTUC potentially improves oncological outcomes. Further prospective studies are needed to clarify the clinical benefit of NAC for locally advanced UTUC.
Evaluating the cost-effectiveness of hydrogel spacer in radiotherapy (RT) of prostate cancer (PC).
Authors: Khairnar Rahul Ramesh , Levy Joseph , Mishra Mark 
Published: February 2018

43 Background: A hydrogel rectal spacer (HRS) is an FDA-approved medical device used to increase the separation between the rectum and the prostate. A recent phase III trial demonstrated a small reduction in the incidence of RT toxicities associated with use of HRS. We conducted a cost-effectiveness analysis of HRS use in PC patients undergoing intensity modulated radiation therapy (IMRT). Methods: A multi-state Markov model was constructed to examine the cost-effectiveness of HRS in men with localized PC receiving IMRT in the US (arms: IMRT alone vs. IMRT + HRS). Subgroups included delivery site of IMRT (hospital vs. ambulatory) and baseline sexual function (SF) (general population vs. those with good SF). Based on previous studies, recurrence and survival were assumed equal for both arms. Data on SF, gastrointestinal and genitourinary toxicities incidence, as well as potential risks associated with HRS implantation were obtained from a recently published clinical trial. Health utilities and costs were derived from the literature and 2018 Physician Fee Schedule. Quality-adjusted life years (QALYs) and costs were modeled for a 5-year period from receipt of RT. Probabilistic sensitivity analysis (PSA) and value-based threshold analysis were conducted. Costs and utilities were discounted at 3% annually. Results: The per-person 5-year incremental cost for HRS administered in a hospital was $4,008 and the incremental effectiveness was 0.0273 QALYs. The incremental cost-effectiveness ratio (ICER) was $146,746 (95% credible interval from PSA $125,638 – $178,049) for PC patients undergoing HRS insertion in a hospital vs. $73,359 ($66,732 – $86,767) for patients undergoing HRS insertion in an ambulatory facility. For men with good SF, the ICER was $55,153 ($46,002 – $76,090) and $26,542 ($17,399 – $46,044) in hospital vs. ambulatory facility. Conclusions: This study is the first to evaluate the cost-effectiveness of HRS based on long-term toxicity data. Based on the current Medicare Physician Fee Schedule, HRS is cost-effective in men with good SF at a willingness to pay threshold of $100,000 and it is marginally cost-effective for the entire population depending on the facility where the HRS is inserted.
Risk-stratified surveillance and cost effectiveness of follow-up after radical cystectomy in patients with muscle-invasive bladder cancer.
Authors: Hatakeyama Shingo , Kusaka Ayumu , Hosogoe Shogo , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2018

430 Background: The cost effectiveness of oncological surveillance after radical cystectomy are not clear. We aimed to develop a risk stratification and a surveillance protocol with improved cost effectiveness after radical cystectomy. Methods: We retrospectively evaluated 581 patients with radical cystectomy for muscle-invasive bladder cancer at 4 hospitals. Patients with routine oncological follow-up were stratified into normal- and high-risk groups by a pathology-based protocol utilizing pT, pN, lymphovascular invasion, and histology. Cost effectiveness of the pathology-based protocol was evaluated and a risk-score-based protocol was developed to optimize cost effectiveness. Risk-scores were calculated by summing risk factors independently associated with recurrence-free survival. Patients were stratified by low-, intermediate-, and high-risk score. Estimated cost per one recurrence detection by the pathology and by risk-scores were compared. Results: Of 581 enrolled patients, 175 experienced disease recurrences. The pathology-based protocol presented significant differences in recurrence-free survival, but the medical expense was high, especially in normal-risk (≤pT2pN0) patients. Cox regression analysis identified six factors that associated with recurrence-free survival. Risk score-based 5-year follow-up was significantly more cost effective than the pathology-based protocol. Conclusions: Risk-score-stratified surveillance protocol has potential to reduce over-evaluation after radical cystectomy without adverse effects on medical cost.
Atezolizumab (atezo) and subsequent therapies in patients (Pts) with metastatic urothelial carcinoma (mUC) outside clinical trials.
Authors: Barata Pedro C. , Koshkin Vadim S. , Mendiratta Prateek , Gopalakrishnan Dharmesh , Karafa Matt , Allman Kimberly D , Martin Allison , Beach Jennifer , Profusek Pam , Tyler Allison Janine , Wood Laura S. , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Grivas Petros 
Published: February 2018

432 Background: The use of immune checkpoint inhibitors (ICI) has revolutionized treatment of mUC. Little is known about the outcomes and safety profile of pts treated with ICI outside of clinical trials, as well as about responses to subsequent therapies. Methods: A retrospective analysis of consecutive mUC pts who received ≥1 dose of atezo 1200 mg every 3 weeks from May 2016 through April 2017 was conducted. Exploratory assessments included overall response rate according to RECIST v1.1, progression-free survival (PFS) and overall survival (OS) since time of treatment initiation, and treatment-related adverse events (TRAE) according to CTCAE v4.03. Results: A total of 79 pts were identified; median age 72 (29-93), 71% men, 27% never smokers, 66% pure urothelial histology, 49% visceral disease, 76% ECOG PS 0-1 and 61% with 1-2 Bellmunt risk factors. Most pts (79%) had primary tumor in bladder, 62% prior surgery and 75% ≥ 1 prior treatment. Most pts (71%) had 1-2 prior lines of treatment, 4% of pts had 3 lines, and 25% of pts had no prior systemic treatment. Pts received a median of 4 atezo doses (1-18) and median treatment duration was 3.2 months (95%CI 1.9-4.5). In 55 pts evaluable for response, 25% had partial response, 36% stable disease and 38% progressive disease, with a median time to best response of 2.7 months (1.3-7.4) and median PFS 4.5 months (95%CI 3.4-5.6). Estimated OS for the entire cohort was 8.3 months (median not reached) and was not significantly different based on prior therapy. TRAE of any grade were noted in 89% of pts and mostly included fatigue (63%) and anorexia (28%). Two pts had grade 4 hyperbilirubinemia, and no toxic deaths were noted. At time of data analysis, 34% of pts remained on atezo, 16% received 1-2 subsequent treatments with median duration of 1.3 months ( 95%CI 0.5-2.2) and 8% PR as best response, 41% were referred to hospice or died, and 9% were lost to follow-up. Conclusions: Pts with mUC treated with atezo had comparable outcomes and toxicity to those reported in clinical trials. Pts who progressed on atezo were unlikely to receive subsequent treatment and the benefit of such treatment was limited. Results may impact clinical trial designs and timing in regard to ICI.
Apparent plasticity in the biological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.
Authors: Seiler Roland , Gibb Ewan , Wang Natalie Qiqi , Oo Htoo Zarni , Lam Hung-Ming , van Kessel Kim E.M , Takhar Mandeep , Erho Nicholas , Winters Brian , Douglas James , Van Rhijn Bas W.G. , Sjödahl Gottfrid , Zwarthoff Ellen C , Thalmann George N. , Davicioni Elai , Boormans Joost L , Dall'era Marc , Van Der Heijden Michiel Simon , Wright Jonathan L. , Black Peter C. 
Published: February 2018

433 Background: After cisplatin-based neoadjuvant chemotherapy (NAC) almost two thirds of patients have residual muscle-invasive bladder cancer (MIBC) present at radical cystectomy (RC). The alterations induced by NAC in these cisplatin-resistant tumors remain largely unstudied. Here, we aim to investigate the characteristics of cisplatin-resistant tumors. Methods: RC samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. In addition, the tumor bed (scar tissue) of 21 post-NAC RC specimens with no residual tumor was profiled. Unsupervised consensus clustering (CC) was performed and the CC were investigated for their biological and clinical characteristics. H&E and immunohistochemistry (KRT5/6, GATA3, KI67 and CD8) were used to confirm tissue sampling and gene expression analysis. Results: Unsupervised consensus clustering yielded four distinct consensus clusters (CC). Consistent basal-(CC1) and luminal-like (CC2) phenotype similar to pre-NAC subtyping was observed in 42% of cases. One third of cases became immune-infiltrated (CC3) in the post-NAC setting but lacked basal and luminal markers. These tumors expressed a strong T-cell signature, chemokine signaling and checkpoint molecules. Conversely, CC4 was associated with healing/scarring. This ‘scar-like’ character of CC4 was consistent with the scar samples. Despite being pathological non-responders, the relative risk of death for CC4 was 2.8 and 3 times less than CC2-Luminal (p = 0.038) and CC3-Infiltrated (p = 0.018), respectively. Luminal-like pre-NAC samples were more likely to adopt a scar-like character (CC4) in the post-NAC setting, while the basal-like tumors were more likely to develop luminal features (CC2). Conclusions: This study expands our knowledge of cisplatin-resistant MIBC by suggesting molecular subtypes to understand the biology of these tumors. Clinical trials are necessary to test the impact of these molecular subtypes with respect to selection of adjuvant and salvage treatments. Post-NAC immune infiltration could have implications for subsequent immunotherapy.
Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial.
Authors: Drakaki Alexandra , Kirby Conor J , Van Der Heijden Michiel Simon , Petrylak Daniel Peter , Powles Thomas , Chi Kim N. , Flechon Aude , Necchi Andrea , Geczi Lajos , Lee Jae-Lyun , Gakis Georgios , Bracarda Sergio , Chowdhury Simon , Lin Chia-Chi , Keizman Daniel , Vaishampayan Ulka N. , Liepa Astra M. , Zimmermann Annamaria , Bell-McGuinn Katherine M , Castellano Daniel E. 
Published: February 2018

434 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have shown objective response rates (ORR) of 15-21% in PD-L1 unselected patients (pts) with platinum-refractory mUC. Overall results of RANGE, a randomized, double-blinded phase 3 trial comparing ramucirumab and docetaxel (R+D) to placebo and docetaxel (P+D) in pts with platinum-refractory mUC demonstrated an ORR of 24.5% to R+D and a statistically significant improvement in progression free survival (PFS; median 4.07 vs 2.76 mo; HR 0.757). Here we present a pre-specified subgroup analysis of pts who received a prior ICI. Methods: RANGE enrolled pts with progressive mUC during or after platinum-based chemotherapy. Additional prior treatment with one ICI was permitted. Pts were randomized (1:1) to receive D 75 mg/m2 up to 10 cycles with R 10 mg/kg or P on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint, investigator-assessed PFS, was analyzed in the first 437 randomized pts. Secondary endpoints included overall survival, objective response, and safety. Radiographic assessment occurred every 6 weeks. Results: Thirty three of the 437 pts (8%) in the PFS population received a prior ICI. The majority (91%) received the ICI immediately following platinum and immediately prior to RANGE. Most pts received atezolizumab (55%) or pembrolizumab (36%); ORR to prior ICI was 6% and the majority (67%) had progressive disease as best response. Median duration of the ICI was 3.5 mo (IQR 1.6-5.2). Disease sites at entry onto RANGE included lymph node (79%), lung (48%), liver (39%) and bone (18%). At data cutoff, responses were achieved by 5/14 (35.7%) on R+D, compared to 2/19 (10.5%) on P+D. Responses to R+D were independent of disease site. Of pts with liver metastases, 3/8 responded to R+D compared to 0/5 on P+D. Overall, median PFS was 5.29 mo on R+D and 2.76 mo on P+D (HR 0.920). The frequency of grade ≥3 adverse events was similar between arms. Conclusions: Acknowledging limitations of sample size, R+D showed higher ORR than P+D in pts who had progressed on platinum and ICI therapy, including those with liver metastases. Clinical trial information: NCT02426125.