bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Aurora kinase A and B expression on response to neoadjuvant chemotherapy and patient outcome in muscle-invasive bladder cancer (MIBC).
Authors: Burgess Earle Frederick , Livasy Chad , Trufan Sally J , Hartman Aaron , Guerrieri Renato , Naso Caroline , Clark Peter E , Grigg Claud , Symanowski James Thomas , Raghavan Derek 
Published: March 2019

393 Background: Identification of robust biomarkers that predict likelihood of benefit from neoadjuvant chemotherapy (NAC) in patients with MIBC remains an unmet need. Previous studies have implicated tumor overexpression of aurora kinases A (AURKA) and B (AURKB) as a mechanism of chemo-resistance. Because overexpression of AURKA has also emerged as a potential biomarker for detection of high-risk urothelial carcinoma, we sought to characterize the expression of AURKA, AURKB with clinical outcomes in MIBC patients who received NAC and to test the hypothesis that tumor overexpression of AURKA and AURKB would predict for residual MIBC. Methods: 47 patients with MIBC who received NAC prior to cystectomy were retrospectively identified. Immunohistochemistry for AURKA and AURKB was performed on pre-treatment diagnostic transurethral resection of bladder tumors and matched cystectomy specimens. Logistic regression models were estimated to determine the impact of pre-NAC expression on pathologic staging at cystectomy. Receiver Operator Characteristic curves (ROC) were calculated to assess diagnostic predictive ability of AURKA and AURKB. AURKA and AURKB were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: 22 of 47 [46.8%] patients had residual muscle-invasive (ypT2-4) urothelial carcinoma after NAC. Neither baseline tumor expression of AURKA (ROC = 0.54, p = 0.71) nor AURKB (ROC = 0.46, p = 0.98) predicted for ypT2-4 status. However, baseline expression of AURKA above the 75th percentile for this cohort, determined by the percentage of tumor cells positive, was associated with an inferior RFS, [HR = 3.79, [1.40, 10.26] p = 0.005] and OS, [HR = 5.84, [2.14, 15.98], p < 0.001]. Similar trends for worse survival outcomes were also observed for high AURKB levels. Conclusions: Although baseline tumor AURKA and AURKB expression did not predict for pathologic residual MIBC after NAC, high expression of AURKA and AURKB predicted for inferior RFS and OS. Further evaluation of AURKA and AURKB as potential biomarkers and therapeutic targets in MIBC is warranted.
Characterization of actionable genetic alterations to guide targeted therapy for metastatic urothelial carcinoma.
Authors: Almassi Nima , Pietzak Eugene J. , Funt Samuel Aaron , Schultz Nikolaus , Dalbagni Guido , Bochner Bernard H. , Al-Ahmadie Hikmat , Bajorin Dean F. , Rosenberg Jonathan E. , Iyer Gopa , Solit David B. 
Published: March 2019

407 Background: Genetic alterations predicting response to targeted therapy are an area of active interest in developing novel therapies for patients with metastatic urothelial carcinoma (mUC). With the objective of characterizing the frequency of actionable alterations (AA) and the evidence supporting targeted therapy for these AAs, we report our experience with next-generation sequencing in mUC. Methods: Patients with sequenced mUC lesions were identified from our prospectively-maintained database. All AAs with clinical or biologic evidence supporting the alteration as predicting response to targeted therapy were identified and stratified by Oncology Knowledge Base (OncoKB) level of evidence (table). The relationship between strength of evidence and administration of targeted therapy was examined. Results: Ninety-nine of 134 patients (74%) harbored at least one AA, with 162 total AAs identified. Twenty level 2B AAs were identified, reflecting the highest level evidence in this cohort, with ERBB2 amplification (9), TSC1/TSC2 (6), and BRCA1/BRCA2 mutations (3) most common. Twenty-eight level 3A, 51 level 3B, and 62 level 4 AAs were also identified. Seventeen patients received targeted therapy, which was administered with greater frequency among patients with level 3B or higher AAs (21% vs 3%). Conclusions: Most patients with mUC harbor at least one AA, suggesting multiple targeted therapeutic opportunities in mUC. These findings highlight the need for additional clinical trials and the role of genetic testing in identifying candidates for targeted therapy. [Table: see text]
Novel perioperative parameters-based nomograms for survival outcomes in upper tract urothelial carcinoma after radical nephroureterectomy.
Authors: Tan Ping , Yang Lu , Xu Hang , Wei Qiang 
Published: March 2019

414 Background: Recently, several postoperative nomograms for cancer-specific survival (CSS) after radical nephroureterectomy (RNU) were proposed, while they did not incorporate the same variables; meanwhile, many preoperative blood-based parameters, which were recently reported to be related to survival, were not included in their models. In addition, no nomogram for overall survival (OS) was available to date. Methods: The full data of 716 patients were available. The whole cohort was randomly divided into two cohorts: the training cohort for developing the nomograms (n = 508) and the validation cohort for validating the models (n = 208). Univariate and multivariate Cox proportional hazards regression models were used for establishing the prediction models. The discriminative accuracy of nomograms were measured by Harrell’s concordance index (C-index). The clinical usefulness and net benefit of the predictive models were estimated and visualized by using Decision curve analyses (DCA). Results: The median follow-up time was 42.0 months (IQR: 18.0-76.0). For CSS, tumor size, grade and pT stage, lymph node metastasis, NLR, PLR and fibrinogen level were identified as independent risk factors in the final model; while tumor grade and pT stage, lymph node metastasis, PLR, Cys-C and fibrinogen level were identified as independent predictors for OS model. The C-index for CSS prediction was 0.82 (95%CI: 0.79-0.85), and the OS nomogram model had an accuracy of 0.83 (95%CI: 0.80-0.86). The results of bootstrapping showed no deviation from the ideal. The calibration plots for the probability of CSS and OS at 3 or 5-year after RNU showed a favorable agreement between the prediction by the nomograms and actual observation. In the external validation cohort, the C-indexes of the nomograms for predicting CSS and OS were 0.79 (95%CI: 0.74-0.84) and 0.80 (95%CI: 0.75-0.85), respectively. As indicated by calibration plots, optimal agreement was observed between prediction and observation in the external cohort. Conclusions: The nomograms developed and validated based on preoperative blood-based parameters were superior to any single variable for predicting CSS and OS after RNU.
Analysis of EGFR mutant upper tract and bladder urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Madison Russell , Gupta Sumati , Ross Jeffrey S. , Schrock Alexa Betzig , Juckett Luke , Miller Vincent A. , Alexander Brian Michael , Pal Sumanta K. , Heymach John , Necchi Andrea , Koyner Jay L , Ali Siraj Mahamed , Chung Jon , Reddy Venkataprasanth P. 
Published: March 2019

416 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFRalt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 66%) and TP53 (58% v 74%) were the most frequently mutated genes in EGFRalt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 63%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFRalt in UTUC than BUC (7/17, 38% v 13/93, 14%; p = 0.01). Compared to other EGFRalt, EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (0% v 100%, p = 5.1E-5; 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.
Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN trial.
Authors: Feng Felix Y , Thomas Shibu , Gormley Michael , Lopez-Gitlitz Angela , Yu Margaret K. , Cheng Shinta , Ricci Deborah S. , Rooney Oliver Brendan , Mainwaring Paul N. , Olmos David , Saad Fred , Chowdhury Simon , Hadaschik Boris A. , Fishbane Nicholas , Davicioni Elai , Liu Yang , Small Eric Jay , Smith Matthew Raymond 
Published: March 2019

42 Background: The SPARTAN trial recently demonstrated that addition of APA to androgen deprivation therapy (ADT) improved metastasis-free survival (MFS) and second progression-free survival (PFS2) in nmCRPC pts. We performed transcriptome-wide profiling of available primary tumor samples from pts in SPARTAN to evaluate potential biomarkers of response or resistance to APA+ADT. Methods: Pts included in SPARTAN were at high risk of developing metastasis.We used a commercially available genomic assay (DECIPHER prostate test, GenomeDx Biosciences, Inc., San Diego, CA) to assess gene expression in 233 archived primary tumors from SPARTAN pts. Using a Cox proportional hazard model, we assessed the association between scores and subtypes from previously derived prognostic and predictive gene signatures, such as DECIPHER and basal (BA) vs luminal (LU) subtyping. Results: Pts with high DECIPHER scores had greater treatment effect with APA+ADT than those with low scores. Pts with LU, a subtype known to be sensitive to ADT, greatly benefited from APA+ADT. Pts with BA, typically resistant to ADT, also benefited from APA+ADT. Conclusions: DECIPHER score and BA or LU subtype may be biomarkers of response to APA+ADT. DECIPHER may be useful for identifying pts for early treatment intensification with APA or other agents, and molecular subtyping may be an effective approach for pt selection in trials combining novel therapies with APA. Clinical trial information: NCT01946204. [Table: see text]
The impact of histologic variants of urothelial carcinoma on clinical outcomes following trimodal bladder-preserving therapy.
Authors: Nagumo Yoshiyuki , Kandori Shuya , Kimura Tomokazu , Kawahara Takashi , Kojima Takahiro , Kawai Koji , Ishikawa Hitoshi , Nishiyama Hiroyuki 
Published: March 2019

421 Background: The current guidelines for muscle-invasive bladder cancer recommend the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. However, a trimodal approach involving the combination of maximal transurethral resection (TUR) and combined chemoradiotherapy is an alternative in selected patients. Clinical outcomes of patients with histologic variants have not well been known. Methods: From 1990 to 2015, 148 patients with cT2-3N0M0 muscle-invasive bladder cancer underwent trimodal bladder-preserving therapy consisting of maximal TUR of the bladder tumor, intra-arterial chemotherapy and radiotherapy at our institution. We compared complete response rate (CRR) of bladder preservation, 5-yr cause-specific survival (CSS), and 5-yr overall survival (OS) for the patients with pure urothelial carcinoma (UC) or variant UC. OS and CSS were analyzed by using the Kaplan-Meier method and log-rank test. Results: The median follow-up was 38.3 months. All patients were T2-T3N0M0 (T2, n = 90; T3, n = 58). There were no significant differences in clinical characteristics between pure and variant UC groups. Eleven (7%) of the 148 patients had variant UC; 7 (64%) had UC with squamous and/or glandular differentiation, and 4 (36%) had other forms, including sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), and clear cell variants (n = 1). There was no significant difference between pure UC and variant UC for CRR of bladder preservation (85% vs 82%, p = 0.66), the 5-yr CSS (88% vs 75%, p = 0.86) and the 5-yr OS (81% vs 75%, p = 0.66). Conclusions: Our findings indicate that trimodal bladder-preserving therapy can be an effective treatment option for selected muscle-invasive bladder cancer patients with variant UC.
Avelumab treatment in metastatic urothelial carcinoma: Post-hoc analysis of high-risk populations in the phase Ib JAVELIN Solid Tumor Study.
Authors: Apolo Andrea B. , Patel Manish R. , Ellerton John Allan , Dirix Luc , Manitz Juliane , Kasturi Vijay , Warth John , Rosen Galit , Gulley James L. 
Published: March 2019

428 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, patients (pts) in various subgroups had a favorable objective response rate (ORR) with avelumab. Here, we report further post hoc analyses of safety and efficacy outcomes with avelumab in high-risk mUC subgroups. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Best overall response (per RECIST 1.1) was adjudicated by an independent review committee. ORR, disease control rate (DCR), progression-free survival (PFS), and adverse event (AE) profiles for pre-specified subgroups of high-risk pts were compared. Results: 242 pts with mUC received avelumab and were followed up for ≥2 years (data cutoff, Apr 2018). No difference was found in ORR between pts with renal insufficiency (creatine clearance [CrCl], <60 mL/min; n=107) and pts with CrCl ≥60 mL/min (n=131; 17.8% [95% CI: 11.0-26.3] vs 15.3% [95% CI: 9.6-22.6]) or between pts with upper (n=56) vs lower tract tumors (n=186; 14.3% [95% CI: 6.4-26.2] vs 17.2% [95% CI: 12.1-23.4]). ORR in pts with baseline liver metastases (n=83) was 6.0% (95% CI: 2.0-13.5) vs 22.0% (95% CI: 15.8-29.3) in pts without (n=159). ORR in elderly pts (≥75 years; n=68) was 25.0% (95% CI: 15.3-37.0) vs 13.2% (95% CI: 8.6-19.2) in younger pts (n=174). ORR in pts with albumin ≥35 g/L (n=197) was 19.8% (95% CI: 14.5-26.1) vs 2.2% (95% CI: 0.1-11.8) in pts with <35 g/L (n=45). Except for the albumin levels and age subgroups (where the trend in ORR was not confirmed), subgroups showed DCR and PFS that were consistent with ORR trends. AE profiles did not exhibit any higher risk of adverse effects in these subgroups. Conclusions: Responses to avelumab occurred in select assessed subgroups previously defined as poor prognostic or high risk, suggesting that immunotherapy may achieve comparable efficacy irrespective of factors such as site of disease and renal status; no difference in safety profiles was identified. Clinical trial information: NCT01772004.
Validation and physiological association of changes in magnetic resonance imaging radiomic features in response to androgen deprivation therapy in patients with high-risk prostate cancer.
Authors: Tharmalingam Hannah , Beasley William , Alonzi Roberto , McWilliam Alan , Hoskin Peter , Choudhury Ananya 
Published: March 2019

43 Background: Biochemical response to neoadjuvant androgen deprivation therapy (nADT) predicts relapse-free and overall survival for prostate cancer (PCa). Radiomic features change in response to nADT, showing potential as prognostic imaging biomarkers. Using multi-parametric MRI (mpMRI) before and after nADT, we aim to validate these changes, evaluate reproducibility and assess their association with previously described ADT-induced reductions in quantitative blood flow (BF) and blood volume (BV) imaging parameters. Methods: 20 patients with high-risk PCa received 4 mpMRI scans, 2 pre-nADT and 2 after 3 months therapy. T2-weighted sequences were used to define tumour regions-of-interest (ROI) which were subtracted from the prostate outline to form the benign prostate ROI. Established kinetic models were applied to dynamic contrast susceptibility MR sequences to derive changes in BF and BV in both ROI. Pyradiomics was used to extract homogeneity and energy features from both ROI. A paired student T-test compared feature values pre- and post-nADT. An inter-class correlation coefficient (ICC) calculated using mean values from consecutive scans assessed reproducibility. Feature changes and physiological parameters were correlated using Pearson’s coefficient. Results: In response to nADT, homogeneity and energy values significantly increased in benign prostate (p < 0.001) and decreased in tumour (p < 0.005). Both features exhibited high reproducibility pre- and post-nADT; all ICC ≥0.89. The reduction in tumour homogeneity and energy showed a positive association with the decline in BF and BV induced by ADT; all r 0.69-0.78, all p < 0.001. No correlation was seen in benign prostate. Conclusions: Energy and homogeneity radiomic features in benign and malignant prostate are reproducible and show significant reciprocal change in response to nADT. Validation of these changes and the strong association in tumour with ADT-induced physiological effects confirms their potential as prognostic biomarkers in high-risk PCa.
First-line PD1/PD-L1 inhibitors for platinum-ineligible advanced urothelial carcinoma (UC).
Authors: Agarwal Archana , Pond Gregory Russell , Drakaki Alexandra , Lee Jae-Lyun , Bilen Mehmet Asim , Di Lorenzo Giuseppe , Grivas Petros , Ornstein Moshe Chaim , Barata Pedro C. , Gupta Shilpa , Hussain Syed A. , Curran Catherine , Garcia Jorge A. , Sonpavde Guru 
Published: March 2019

432 Background: FDA modified the label for the use of 1st-line pembrolizumab or atezolizumab therapy to PD-L1 high cisplatin-ineligible or platinum-ineligible UC patients (pts) regardless of PD-L1 expression. However, the outcomes when using PD1/PD-L1 inhibitors for platinum-ineligible pts are unclear. We conducted a retrospective study to evaluate clinical outcomes with first-line PD1/PD-L1 inhibitors for platinum-ineligible pts with advanced UC in a real-world setting. Methods: We collected data retrospectively from 6 institutions. The following criteria were deemed to render pts platinum-ineligible although physician discretion was also allowed: Cr Cl < 30 ml/min, ECOG-PS 3, Both Cr Cl 30 to < 60 AND ECOG-PS 2. Demographic and clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. A Cox regression analysis was done to study the association of baseline variables with response and survival. Results: Data were available for 45 pts. Pts received atezolizumab [n = 24], pembrolizumab [n = 11], nivolumab [n = 7] and durvalumab [n = 3]. The mean age was 72.2 (range 45-90) years. The reasons for platinum-ineligibility were: Cr Cl < 30 ml/min (n = 17), ECOG-PS 3 (n = 3), ECOG-PS 2 plus Cr Cl < 60 ml/min (n = 7), elderly with co-morbidities (n = 12), and reason was unavailable for 6 pts. The median OS was 37 weeks (CI 30-80). ORR was 27.3%: Complete response in 3 pts [6.8%], partial response in 9 pts [20.5%], stable disease in 11 pts [25%] and progressive disease in 21 pts [47.7%] and data for 1 patient was unavailable. Toxicity of any grade were seen in 42.2% of pts and Grade ≥3 toxicity in 9 pts’ [20%]. There were no treatment-related deaths. Anemia (HR = 0.75, 95% CI 0.62 - 0.92, P = 0.005) and liver metastasis (HR = 1.17, 95% CI 0.47 - 2.93, P = 0.017) correlated with shorter OS. Conclusions: To our knowledge, this is the 1st report of efficacy and toxicity of PD1/PD-L1 inhibitors as1st-line therapy for platinum ineligible UC. Data appear comparable to those reported previously in unselected cisplatin-ineligible pts receiving pembrolizumab or atezolizumab in phase II trials. Validation is needed in larger datasets and prospective trials.
Blood myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) are correlated with neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS).
Authors: Sheng Iris Yeong- Fung , Diaz-Montero C. Marcela , Rayman Patricia A. , Wei Wei (Auston) , Fallah Jaleh , Finke James , Kim Jin Sub , Pavicic Paul G. , Lamenza Marcelo , Company Donna , Stephenson Andrew J. , Campbell Steven , Haber Georges-Pascal , Lee Byron H , Mian Omar Y. , Gilligan Timothy D. , Rini Brian I. , Garcia Jorge A. , Grivas Petros , Ornstein Moshe Chaim 
Published: March 2019

436 Background: MDSC have been linked to the chronic inflammatory microenvironment of tumor cells and pathologic outcomes in UC patients (pts) undergoing cystectomy. NLR is an established inflammatory biomarker with prognostic properties in mUC. We hypothesized that MDSCs correlate with NLR and OS in mUC. Methods: MDSCs were measured in blood samples from mUC patients by fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UC-MDSC: CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells from PB and absolute numbers from WB. Spearman’s correlation assessed correlations between MDSC & NLR. Kaplan Meier curves and log rank test estimated OS from the time of MDSC collection to last follow up or date of death. Results: Of 79 pts, 77% were men and 42% were never smokers with a median age of 69 (31-83). Overall, 71% had pure UC and 81% had lower tract UC. Prior therapies include intravesical therapy (22%), neoadjuvant chemotherapy (31%), and cystectomy/nephroureterectomy (61%). Median follow up was 12 months (range: 0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p≤0.001). Negative correlation was noted between NLR and WB UC-MDSC:PMN-MDSC ratios (rho = -0.27, p = 0.03), as well as NLR and PB UC-MDSC:PMN-MDSC (rho = -0.28, p = 0.02). Median survival was 17.7 months (95% CI: 11.0-NA months). Overall 1-yr and 3-yr survival were 0.60 (95% CI: 0.49-0.73) and 0.15 (95% CI: 0.03-0.67), respectively. Higher WB UC-MDSC levels were associated with shorter OS (HR 2.85, 95% CI: 1.43-5.65, p = 0.003). Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UC-MDSC levels have negative prognostic roles for OS. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow up are needed.