bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory markers at baseline (C1) and cycle 3 (C3) and their association with clinical outcomes 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 , Kucuk Omer , Carthon Bradley Curtis , Master Viraj A. , Bilen Mehmet Asim 
Published: March 2019

390 Background: Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) have been explored as biomarkers for response to IO. We investigated the association between these biomarkers and clinical outcomes in urothelial cancer pts treated with IO. Methods: We conducted 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 clinical or radiographic progression, respectively. MLR, NLR, and PLR were collected at C1 and C3. The nonlinear relationship between log-transformed biomarkers and OS or PFS was examined by martingale residual plot and optimal cutoff (OC) values were determined. Multivariable analysis (MVA) used Cox proportional hazard model. Results: OC for C1 and C3 NLR, MLR, and PLR were 2.06 and 1.42, -0.331 and -0.153, and 5.7 and 5.6, respectively. Pts with C1 NLR and PLR above OC had worse OS and shorter PFS (all p<0.05) (Table). High C3 MLR portended shorter OS and PFS. NLR, MLR and PLR were highly correlated (Pearson correlation coefficients ≥ 0.67, p<0.0001). Conclusions: High NLR, MLR, and PLR at C1 and at C3 are associated with worse clinical outcomes in this cohort. These values warrant a larger study for validation. MVA† of MLR, NLR, and PLR at C1 and at C3 with OS and PFS. [Table: see text]
First survival outcomes and additional secondary analyses from PURE-01: Pembrolizumab (pembro) before radical cystectomy (RC) in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Necchi Andrea , Bandini Marco , Gallina Andrea , Bianchi Marco , Raggi Daniele , Farè Elena , Messina Antonella , Chung Jon , Ali Siraj Mahamed , Madison Russell , Anichini Andrea , Colecchia Maurizio , Gandaglia Giorgio , Fossati Nicola , Scuderi Simone Luca Antonio , Pederzoli Filippo , Colombo Renzo , Briganti Alberto , Montorsi Francesco 
Published: March 2019

391 Background: PURE-01 is a phase 2 study of Pembro before RC in MIBC: the primary endpoint (pathologic complete response [pT0]) was met in advance ( Necchi et al. JCO 2018). While the study is still recruiting patients (pts), we analyzed the interim long-term outcomes in terms of relapse-free survival (RFS) and the role of multiparametric bladder magnetic resonance imaging (mpMRI) in predicting major pathologic response (pT<2) in RC. Methods: Pts with clinical stage T2-3bN0M0 received 3 courses of 200mg Pembro, before RC. Pts were staged and re-assessed with mpMRI before RC. 1-y RFS (overall and by pathologic stage) after Pembro and RC was compared with that from clinical stage-matched cohort of San Raffaele Urological Institute (URI, n=1021) and of the RISC multicenter database (n=719, Bandini et al, Eur Urol Oncol 2018). mpMRI were performed in all pts through bladder catheterization. The apparent diffusion coefficient (ADC) changes post-Pembro were matched with pathologic response, qPCR and genomic data from RC samples (FoundationONE). Results: 70 pts have completed treatment thus far: with 27 pT0 (38.6%) and 44 pT<2 (62.9%), activity was confirmed. 21 pts had ≥1y follow-up and were analyzed. Overall, 1-y RFS (95% CI) in PURE-01, URI and RISC were: 95.2 (86.6-100), 79.0 (76-82), and 69.7 (66.2-73.4). 1-y RFS after neoadjuvant chemotherapy and RC in URI and RISC were: 76.7 (61-97), and 76.5 (71-83). 1-y RFS for pT3-4 and/or pN+ pts were: 88.9 (71-100), 71.2 (67-76), and 57.1 (52-62). 39/70 pts had measurable disease for pre-post mpMRI changes. Pts with pT<2 (n=16) on RC showed a median “mean ADC” of 0.98 mm2/s vs 0.84 mm2/s of non-responders (NR, n=23, p=0.098), despite an increased T-cell infiltrate. Pts with cell-cycle gene alterations in RC (n=8) were all NR and showed lower median “mean ADC” values (p=0.074). Conclusions: The early efficacy data further support the role of single-agent IO as neoadjuvant therapy in MIBC. Pembro may be beneficial at long-term also in pathologically high-risk pts, thus questioning the value of PD-L1 for pt selection. mpMRI and genomic data might help identifying those pts who may need re-TURB only instead of RC. Clinical trial information: NCT02736266.
Association of next generation sequencing characteristics of MIBC specimens with clinical outcomes: The USC experience.
Authors: Basu Arnab , Chang Jeremy , Haiber Karen , Dorff Tanya B. , Pinski Jacek K. , Quinn David I. , Sadeghi Sarmad 
Published: March 2019

397 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease. Several molecular subtypes have been identified. Commercial next generation sequencing (NGS) panels now provide significant genetic information on tumors. We conducted an exploratory analysis on MIBC tumor samples at our institution with commercial NGS data to evaluate if these assays provide novel prognostic information. Methods: NGS data (FoundationOne) from all locally advanced and metastatic bladder specimens were collected and combined with information on demographics, tumor characteristics (stage, grade, histology). Overall Survival (OS), post-cystectomy disease free survival (DFS), and Progression Free Survival (PFS) data were also compiled. Mutations in 353 genes were examined for alterations in TP53, Rb, FGF3-RAS-RAF and PI3K-mTOR-AKT pathways. Results: 48 samples were analyzed. Most samples were pure TCC (68.8%) followed by Squamous (16.8%) , Adenocarcinoma (6.3%), Small Cell (6.3%) and Plasmacytoid variants (2.1%). Most patients (91.5%) were locally advanced at diagnosis. Pathologic alterations were found in TP53 (54.2%) , Rb (60.4%), FGF3-RAS-RAF(89.6%) and PI3K-mTOR-AKT(70.8%) pathways. Squamous variants were more likely to have TP53 pathway alterations compared with others (100% vs 45% , p < 0.001) and predicted for poor overall survival. TP53 exons did not predict outcomes. In multivariable adjusted cox-regression models Rb alterations appeared to predict for improved post cystectomy DFS (p = 0.01). TP53 mutations predicted for worse PFS (p=0.01) while PI3K-mTOR-AKT pathway alterations were associated with poorer OS (p=0.02) after adjusting for all other predictors. Conclusions: In this limited single institution sample analyzed by commercial available NGS panels, some prognostic information was available. Analysis of a larger population could result in the validation of other predictive or prognostic markers.[Table: see text]
Circulating cellular biomarkers associated with delayed time to progression among bladder cancer patients treated with immune checkpoint inhibitors.
Authors: Koshkin Vadim S , Friedlander Terence W. , Li Patricia , Schonhoft Joseph , Krupa Rachel , Richardson Robin , Ontiveros Priscilla , Wang Yipeng , Dittamore Ryan , Paris Pamela 
Published: March 2019

398 Background: Circulating tumor cells (CTCs) are an important emerging biomarker in bladder cancer that allow for a minimally invasive assessment of tumor activity and response to treatment. Characterization of CTC and other single cell populations associated with improved clinical outcomes can help guide treatment recommendations for patients with metastatic bladder cancer. Methods: Patients with metastatic bladder cancer who received treatment with anti-PD-1 or anti-PD-L1 agents were enrolled in this study. Patient response to treatment was assessed by treating physicians according to RECIST v1.1. Blood samples were prospectively collected from patients prior to the initiation of therapy and then while on treatment and shipped to Epic Sciences for processing. All nucleated cells were subjected to immunofluorescent (IF) staining and CTC and leukocyte identification by fluorescent scanners using algorithmic analysis. Kaplan-Meier analysis was utilized to compare time to progression of patients whose CTC and leukocyte values were above and below several pre-determined parameters. Results: A total of 27 patients (median age 74 years, 70% male) were enrolled in this study and were treated with anti-PD-1/PD-L1 agents pembrolizumab (n=15), atezolizumab (n=11), or nivolumab (n=1). For 20 patients who had evaluable responses, objective response rate (ORR) was 2/20 (10%), all partial responses; another 5/20 (35%) had stable disease. Increased CD4% (>8% of total leukocytes) was associated with delayed time to progression (TTP) (p=0.002) whereas increased baseline total CTCs (>2) had a statistically non-significant trend towards shorter TTP (p=0.09). Baseline CD8%, CD4/CD8 ratio and CTC PD-L1 status were not associated with TTP. Conclusions: In a preliminary analysis among metastatic bladder cancer patients treated with immune checkpoint inhibitors, patients with an increased baseline CTC count had a statistically non-significant trend towards shorter TTP whereas increased baseline CD4 cells had an association with delayed TTP. This prospective study is ongoing, and the results will be further validated in larger patient cohorts.
Impact of putative chemopreventative agents on prostate cancer diagnosis.
Authors: Goldberg Hanan , Moshin Faizan , Klaassen Zachary William Abraham , Chandrasekar Thenappan , Wallis Christopher , Herrera Cáceres Jaime Omar , Ahmed Ardalan , Woon Teck Sing , Kulkarni Girish S. , Berlin Alejandro , Saskin Refik , Hamilton Robert James , Alibhai Shabbir M.H. , Fleshner Neil Eric 
Published: March 2019

40 Background: Prostate cancer (PC) is the most common non-cutaneous cancer in Canadian men and the third most common cause of cancer death in Canada. Several studies have shown that use of commonly prescribed medications, including those used for diabetes and hypercholesterolemia, is associated with improved survival in various malignancies, including PC. There has not been any large population-based study, examining the effects of these and other commonly prescribed medications, on the rate of PC diagnosis, over a 20 years follow-up period. Methods: A retrospective population-based study using data from the institute of clinical evaluative sciences, including all male patients aged 65 and above in Ontario who have had a negative first prostate biopsy between 1994 and 2016. We assessed the impact of commonly prescribed medications on PC diagnosis. The medications included Statins (hydrophilic and hydrophobic), diabetes drugs (metformin, insulins, sulfonylureas, and thizolidinedions), proton pump inhibitors, 5 alpha reductase inhibitors, and alpha blockers. Time dependent Cox regression proportional hazards models were performed determine predictors of PC diagnosis. Medication exposure was time varying and modeled as “ever” vs. “never” use or as cumulative exposure for 6 months of usage. A priori variables included in the model included age, ADG comorbidity score, rurality index, index year, and all medications. Results: A total of 51,415 men were analyzed over a mean (SD) follow-up time of 8.06 (5.44) years. Overall, 10,466 patients (20.4%) were diagnosed with PC, 16,726 (32.5%) had died, and 1,460 (2.8%) patients died of PC. On multivariable analysis increasing age and rurality index were associated with higher PC diagnosis rate, while a more recent index year, and usage of hydrophilic statins was associated with a lower diagnosis rate in both “ever” vs. “never” and cumulative models (HR 0.832, 95% CI 0.732-0.946, p = 0.005, HR 0.973 95% CI 0.951-0.995, p = 0.016, respectively). Conclusions: Hydrophilic statins are associated with a clinically significant lower PC diagnosis. To our knowledge this is the first study demonstrating a clear advantage of one group of statins (hydrophilic) over another (hydrophobic) in PC prevention.
Is the occurrence of higher adverse effects associated with better oncological outcome in metastatic urothelial carcinoma patients treated with pembrolizumab?
Authors: Hayakawa Nozomi , Kikuchi Eiji , Ogihara Koichirou , Hattori Seiya , Yoshimine Shunsuke , Shirotake Suguru , Okabe Takashi , Yamashita Ryo , Oya Mototsugu 
Published: March 2019

405 Background: Pembrolizumab is an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody and a recently approved and long-awaited drug for the treatment of metastatic urothelial carcinoma (UC). It is an immune checkpoint inhibitor, which has been shown to trigger new autoimmune disorders. We investigated the association of occurrence of adverse effects (AE) with clinical outcome in Japanese UC treated with pembrolizumab. Methods: We identified 50 cases treated with pembrolizumab for chemo-resistant UC between December 2017 and August 2018 at our 5 institutions. Pembrolizumab-induced AE were reported by using Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. We evaluated the association between pembrolizumab-induced AE and response rate as well as patient survival. Results: The median age of the patients was 73 years (range, 46-89 years). The male/female ratio was 36/14. The primary tumor location was the pelvis in 10, ureter in 10, and bladder in 30. The median course of pembrolizumab was 4 (1-11). In the 50 patients, 36 AEs were observed, 11 of which were classified as CTCAE grade 2/3 . These patients were defined as the high AE groups. No grade 4 AE was encountered. In the high AE groups the most common AE was adrenal dysfunction (n = 4). Patients with no or CTCAE grade 1 were defined as the no/low AE groups. In the 45 cases who had measurable lesions, at the point of maximum effect the sum of the target lesion longest diameter (SLD) was decreased in 17 cases (37.8%) compared to baseline. SLD decreased in 7 (70%) patients in the high AE groups, which was significantly lower than those in the no/low AE groups (10, 28.6%, p = 0.027). The disease control rate defined by RECST ver. 4.0 at best response in the high AE groups was 81.8%, which was significantly higher than that in the no/low AE groups (46.2%, p = 0.046). The 6-month progression-free survival rate and the 6-month cancer-specific survival rate for the high AE groups was not different from that for the no/low AE groups. Conclusions: In patients with metastatic UC, the occurrence of CTCAE grade 2/3 might be associated with a better clinical response to pembrolizumab treatment.
A phase I study to assess the safety and tolerability of intravesical pembrolizumab in recurrent non-muscle invasive bladder cancer (NMIBC).
Authors: Woodcock Victoria K , Purshouse Karin , Butcher Chrissie , Haddon Caroline , Verrall Gillian , Elhussein Leena , Salio Mariolina , Middleton Mark R. , Cerundolo Vincenzo , Crew Jeremy , Protheroe Andrew 
Published: March 2019

406 Background: Intravesical BCG has been the mainstay of therapy following TURBT for intermediate risk NMIBC for many years and is thought to act through activation of non-specific local immunity. With the recent success of checkpoint inhibitor treatment in metastatic bladder cancer, we sought to investigate the anti-PD1 inhibitor pembrolizumab as a potential agent for use in patients with intermediate risk NMIBC in a phase I/II study. The primary aim of the phase I safety run-in was to assess the safety and tolerability of intravesical pembrolizumab after TURBT in patients with intermediate risk NMIBC. Methods: Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, ECOG PS 0-1 and adequate end organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of 6 doses. Intra-patient dose escalation was performed in three paired patient cohorts with doses starting at 50mg and increasing through 100mg to a maximum of 200mg. Adverse events (AEs) were assessed using CTCAE v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug related, grade 4 haematological or ≥ grade 3 non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results: In the first 4 patients treated, no DLTs were seen during dose escalation. Drug-related AEs included Grade 1 dysuria, fatigue and nausea. Grade 1-2 urinary tract infections, Grade 1 cystitis and Grade 3 urosepsis (SAE) were observed but assessed as probably not related to pembrolizumab. Recruitment of a final cohort of two patients at repeated doses of 200mg is ongoing to confirm safety and tolerability of this dose. Conclusions: Administration of intravesical pembrolizumab was safe and well tolerated in patients with NMIBC following TURBT. A randomised, parallel group, phase II marker-lesion study to assess the safety, efficacy and tolerability of either intravesical pembrolizumab or intravenous pembrolizumab in a larger cohort of patients with intermediate risk recurrent NMIBC is planned. Clinical trial information: NCT03167151.
Analysis of the National Cancer Data Base (NCDB) on impact and trend of neoadjuvant chemotherapy in upper urinary tract urothelial cancer.
Authors: Khan Rashad , Huang Danning , Basnet Alina 
Published: March 2019

408 Background: Five year cancer specific survival rate is between 12- 70% for pT2 and higher UUTUC tumors. Adjuvant platinum based therapies have proven to improve Overall survival (OS) in observational series. Compromised renal function after surgery, delayed recovery from surgery pose challenge for adjuvant chemotherapy (AC). Thus, neoadjuvant chemotherapy (NAC) is an appealing option. However, there is only limited evidence on the role of NAC in UUTUC. Methods: We conducted a retrospective study of UUTUC (stage I- III) who underwent complete or partial nephroureterectomy with peri-operative chemotherapy. We then compared OS outcome among NAC vs AC groups. OS was calculated using Kaplan Meier analysis. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 50539 UUTUC patients reported in NCDB (2004-2016), 20121 met our inclusion criteria. 360 patients received NAC, 2617 received AC and 17144 received only surgery. Patients who received NAC were more likely to be younger, treated at academic centers, have Medicare and private insurance, have clinical T3 and higher tumor, have lower Charlson-Deyo Score (CDCC) score and undergo complete nephroureterctomy. One, three and five year OS among NAC and AC is depicted in table 1. With 150 months (m) follow up, median OS was 73.89 m for NAC and 54.14 m for AC group. A log rank test with p value=0.3437 shows no significant difference in survival rates of the two groups. Though consistent upward trend is observed in the use of NAC from 2004 to 2015, significantly higher percentages of patients still undergo only surgery without perioperative chemotherapy. Conclusions: Numerically higher mOS in NAC group was not statistically significant different from AC group. Use of perioperative chemotherapy appears to be much lower in UUTUC. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration of chemotherapy, and provider/patient selection bias. Overall survival among two groups. [Table: see text]
Fierce-21: Phase II study of vofatmab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).
Authors: Necchi Andrea , Castellano Daniel E. , Mellado B , Pang S , Urun Yuksul , Park Se Hoon , Vaishampayan Ulka N. , Currie Graeme , Abella-Dominicis Esteban , Pal Sumanta K. 
Published: March 2019

409 Background: Patients (pts) with mUC who have failed platinum-based chemotherapy have a poor prognosis. About 20% of them usually respond to immune checkpoint inhibitors (ICI). Also, 20% of pts with mUC harbor FGFR3 mutations or fusions (M/F), and this feature may be associated with lower sensitivity to ICI. Vofatamab (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VM) or in combination with docetaxel (VD). Methods: The study consists of a P 1b lead-in (P1b with VD), previously reported followed by P2 expansion cohort in FGFR3 M/F+ pts (identified with the FoundationONE CDx™ assay on archival samples). The study enrolled mUC pts with failure to ≥ 1 line prior chemotherapy (including prior taxane treatment) or ≤12 months of (neo)adjuvant chemotherapy, measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone (VM) and in combination with D (VD) at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and activity (objective response-rate [ORR]). Results: 55 pts have received treatment. In the Ph 2 study, 21 pts received VM, 15 pts received VD. 35% of pts were included as 2nd line therapy, 65% in 3rd or later line of treatment. For pts receiving VD, safety was consistent with Ph 1B data. For pts receiving VM, median age was 67 yrs, ECOG 1 = 71.4%, Hgb < 10 gm/dL 13%, liver metastases 19%, ≥ 2 prior regimens 57%, (best response to prior therapy PD 31%). TEAEs occurring in ≥5% patients were asthenia (19%), diarrhea (9.5%), flushing 14%, chills (9.5%), hypotension (9.5%), decreased appetite (19%) and creatinine increased (9.5%). The majority of TEAS were grade 1 and 2. Only 1 patient on MF had a grade 3 TEAE and only 1 patient discontinued treatment due to an AE. The ORR have been seen in 7 pts to date including those receiving both VM and VD. Conclusions: Vofatamab both alone and combined with D in an every 3-week schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VM and VD have demonstrated efficacy in terms of ORR, and mature results with PFS data will be presented. Clinical trial information: NCT02401542.