bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-reported outcomes of patients with advanced renal cell carcinoma (aRCC) treated with first-line nivolumab plus cabozantinib versus sunitinib: The CheckMate 9ER trial.
Authors: Cella David , Choueiri Toni K. , Blum Steven I. , Ejzykowicz Flavia , Hamilton Melissa , Zhang Joshua , Ivanescu Cristina , Motzer Robert J. 
Published: March 2021

285 Background: In the phase III, open-label CheckMate 9ER trial (NCT03141177), patients with aRCC were randomized 1:1 (stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk score, tumor programmed death ligand 1 expression, geographic region) to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328) for first-line treatment until disease progression or unacceptable toxicity (max N treatment, 2 years). N+C met primary and secondary efficacy endpoints by significantly improving progression-free survival, overall survival, and objective response rate versus S in aRCC patients with a clear cell component. Here, we present in-depth health-related quality of life (HRQoL) patient-reported outcome (PRO) results, including overall between-group comparisons of treatment groups and time to confirmed deterioration (TCD). Methods: PROs in all randomized patients were an exploratory endpoint assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19) and EQ-5D-3L instruments. PRO assessments at baseline, common on-treatment scheduled visits, and common follow-up visits for both arms were analyzed. Changes from baseline were assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors. TCD was calculated from Kaplan–Meier estimates and Cox proportional hazards models. Results: Median follow-up for overall survival was 18.1 months. PRO completion rates were > 90% at baseline, and ≥ 80% at all on-treatment assessments (≥ 10 patients) through week 91 in both arms. The overall least squares mean difference in change from baseline favored N+C over S in FKSI-19 (all domains) and in EQ-5D-3L. Patients treated with N+C experienced less treatment burden, with decreased risk of confirmed deterioration across most measurements versus S, including FKSI-19 total, disease-related symptoms (DRS), DRS-physical (DRS-P), DRS-emotional (DRS-E), functional well-being (FWB), and EQ-5D-3L visual analog scale (VAS) scores (Table). Conclusions: Patients reported statistically significant HRQoL benefits with N+C versus S. Treatment with N+C significantly reduced the risk of deterioration in HRQoL scores, including in disease-related symptoms of kidney cancer. These results suggest that the superior efficacy of N+C over S comes with the additional benefit of improved HRQoL. Clinical trial information: NCT03141177 . [Table: see text]
Analysis of plasma KIM-1 as a biomarker for recurrence risk after resection for localized renal cell carcinoma.
Authors: Xu Wenxin , Puligandla Maneka , Halbert Brian , Haas Naomi B. , Flaherty Keith , Uzzo Robert Guy , Dutcher Janice P. , DiPaola Robert S. , Sabbisetti Venkata , Bhatt Rupal Satish 
Published: March 2021

342 Background: Recurrence is common after nephrectomy for renal cell carcinoma (RCC), but no circulating biomarkers are available to identify patients at highest risk of recurrence who may benefit from adjuvant therapy. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. Methods: Banked plasma samples were analyzed from the ECOG-ACRIN 2805 (ASSURE) trial evaluating adjuvant sunitinib, sorafenib, and placebo in resected high-risk RCC. KIM-1 levels were measured at trial enrollment 4-12 weeks post-nephrectomy (baseline) and on cycle 2 day 1 (C2D1) using a previously validated microbead assay. A lognormal accelerated failure time model was used to test for association between circulating KIM-1 and disease-free survival (DFS). Results: Plasma samples from 418 patients were analyzed. In univariable and multivariable analyses, higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms. This association remained independently significant after adjustment for Fuhrman grade, T-stage, N-stage, and tumor histology (survival time ratio 0.56 for 75th vs 25th percentile of KIM-1, 95% CI 0.42-0.73, p < 0.001). The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement. The addition of baseline KIM-1 improved the concordance of both the SSIGN and UISS prognostic models (SSIGN concordance 0.57 vs 0.43, p = 0.05; UISS concordance 0.60 vs 0.40, p = 0.0005). C2D1 KIM-1 was not an independent predictor for DFS after adjusting for baseline KIM-1. Conclusions: Elevated plasma KIM-1 level at post-nephrectomy baseline is associated with worse DFS in RCC. This is consistent with the hypothesis that post-nephrectomy plasma KIM-1 may be a biomarker for microscopic residual disease. The model was additionally adjusted for papillary and chromophobe histology, sex, and ECOG performance status. [Table: see text]
Social disparities in the diagnosis and management of bladder cancer.
Authors: Hasan Shaakir , Lazarev Stanislav , Garg Madhur , Press Robert H. , Chhabra Arpit , Choi Isabelle , Simone Charles B. , Gorovets Daniel , Mehta Keyur J. 
Published: March 2021

403 Background: The socioeconomic characteristics associated with the diagnosis and management of bladder cancer are not well described. Methods: We utilized the National Cancer Database (NCDB) to stratify cases of urothelial cell carcinoma of the bladder by the National Comprehensive Cancer Network (NCCCN) guidelines: early (Tis, Ta, T1), muscle invasive (T2-T3, N0), locally advanced (T4, N1-3), and metastatic. We then used multivariate binomial and multinomial logistic regression analyses to identify demographic characteristics associated with stage at diagnosis and receipt of cancer-directed therapies. Hazard ratios (HR) are reported with 95% confidence intervals. Results: After exclusions, we identified 331,714 early, 72,154 muscle invasive, 15,579 locally advanced, and 15,161 metastatic cases. Relative to diagnosis at early stage, the two strongest independent predictors of diagnosis at muscle invasive, locally advanced, and metastatic disease included black race (HR = 1.19 [1.15-1.23], HR = 1.49 [1.40-1.59], HR = 1.66 [1.56-1.76], respectively), and female gender (HR = 1.21 [1.18-1.21], HR = 1.16 [1.12-1.20], and HR = 1.34 [1.29-1.38], respectively). Additional demographic factors associated with diagnosis at a more advanced stage on multivariable analysis included older age, treatment at an academic center (except for metastasis), Medicaid insurance, and patients from lower income/ less educated/more rural areas (all p < 0.01). The following demographic factors were less likely to receive cancer-directed therapies, signified by odds ratios, per multivariable binomial regression analysis: Additionalyl, female patients (HR = 1.03, 1.02-1.05) and black patients (HR = 1.13, 1.11-1.16) were the only demographic correlates of reduced survival in the entire cohort with multivariable cox regression analysis. Conclusions: In the largest study of its kind, we report that several socioeconomic, racial, and gender factors are associated with the diagnosis of bladder cancer at a later stage, as well as the use of less cancer-directed treatments. Further investigation is warranted to better characterize, and ultimately improve upon, health disparities in bladder cancer. Research Sponsor: None[Table: see text]
Post-hoc analysis of long-term outcomes in patients with CR, PR, or SD to pembrolizumab (pembro) or platinum-based chemotherapy (chemo) as 1L therapy for advanced urothelial carcinoma (UC) in KEYNOTE-361.
Authors: Loriot Yohann , Alva Ajjai Shivaram , Csőszi Tibor , Ozguroglu Mustafa , Matsubara Nobuaki , Geczi Lajos , Cheng Susanna Y. , Fradet Yves , Oudard Stephane , Vulsteke Christof , Morales-Barrera Rafael , Flechon Aude , Gunduz Seyda , Rodriguez-Vida Alejo , Mamtani Ronac , Yu Evan Y. , Liu Chih-Chin , Imai Kentaro , Homet Moreno Blanca , Powles Thomas 
Published: March 2021

435 Background: The phase III KEYNOTE-361 study compared efficacy and safety of 1L pembro + chemo or pembro vs chemo in pts with advanced UC. The trial did not meet its primary endpoints of PFS or OS superiority for pembro + chemo vs chemo; formal testing for OS for pembro vs chemo was not performed. We present a post hoc landmark analysis to examine the durability of CR/PR/SD and long-term survival in pts with CR, PR, or SD to pembro vs chemo at week 9 in KEYNOTE-361 (NCT02853305). Methods: Landmark analyses of OS by CR/PR/SD at 9 weeks after randomization in the ITT population were performed. Pts were included if they had a best response of CR/PR/SD per RECIST v1.1 by blinded independent central review at the landmark date of week 9 (first imaging assessment per study protocol). Duration of CR/PR/SD and OS were estimated by the Kaplan-Meier method. No formal comparisons were performed. Results: 307 pts were randomized to receive pembro and 352 pts to receive chemo in the KEYNOTE-361 study. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 32.5 (22.0-42.4) mo for the pembo arm and 31.4 (22.1-41.6) mo for the chemo arm. In the landmark analysis, fewer pts had CR/PR/SD at week 9 with pembro (n=137 [45%]) than with chemo (n=253 [72%]). Median (range) duration of response for pembro vs chemo was 18.7 (4.4+-35.4+) vs 12.3 (0.0+-29.7+) mo for pts with CR, and 35.0 (1.1-36.1+) vs 6.1 (0.0+-36.3+) mo for pts with PR. Median (range) duration of SD was 4.8 mo (0.0-38.2+) with pembro and 4.6 mo (0.0-16.1+) with chemo. Median OS (95% CI) for pembro vs chemo was not reached (NR) (25.5-NR) vs NR (19.1-NR) for pts with CR; NR (NR-NR) vs 14.8 mo (12.1-21.0) for pts with PR; and 18.5 mo (13.8-28.8) vs 11.1 mo (8.1-14.6) for pts with SD, respectively. Long-term OS rates were higher with pembro vs chemo across all groups (CR/PR/SD) at week 9 (Table). Conclusions: In this post hoc landmark analysis, chemo was associated with more initial responses than pembro, whereas pembro was associated with longer median duration of CR and PR, and generally longer median OS than chemo. Among pts who achieved CR/PR/SD at week 9, the relative OS benefit for pembro vs chemo increased over time. Clinical trial information: NCT02853305. [Table: see text]
Heterogeneity in Nectin-4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin.
Authors: Chu Carissa , Sjöström Martin , Egusa Emily A , Gibb Ewan , Badura Michelle L , Koshkin Vadim S , Stohr Bradley A. , Meng Maxwell , Pruthi Raj , Friedlander Terence W. , Lotan Yair , Black Peter C. , Porten Sima P. , Feng Felix Y , Chou Jonathan 
Published: March 2021

463 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4 (encoded by the PVRL4/NECTIN4 gene ) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In the present study, we sought to 1) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and 2) determine if Nectin-4 expression mediates EV sensitivity or resistance. Methods: NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1912 total patients) were used to compare relative NECTIN4 expression across molecular subtypes. The outcome of the gene expression analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in multiple bladder cancer cell lines. NECTIN4 was stably over-expressed or knocked down in basal (TCCSUP and UMUC-3) and luminal (HT-1376, HT-1197 and UMUC-9) bladder cancer cell lines, respectively, and EV dose-response assays were performed, as measured by cell proliferation and clonogenic assays. Results: NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes (p < 0.001). NECTIN4 expression is positively correlated with the luminal markers GATA3, FOXA1, and PPARG across cohorts (Spearman’s rank correlation r = 0.57, p < 0.0001 for GATA3, r = 0.37, p < 0.0001 for FOXA1, and r = 0.56, p < 0.0001 for PPARG). NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 led to EV resistance, and EV-resistant cell lines expressed decreased levels of Nectin-4. Conclusions: Results of this pre-clinical study suggest that sensitivity to EV is mediated by expression of NECTIN4, which is significantly enriched in luminal subtypes of bladder cancer. Downregulation of NECTIN4 leads to resistance to EV. These findings have implications for biomarker development, patient selection and the inclusion of molecular subtyping in ongoing and future EV clinical trials. Further investigation into Nectin-4 loss as a mechanism of resistance in patients treated on EV is warranted.
A developmental lineage-based gene co-expression network for mouse pancreatic β-cells reveals a role for Zfp800 in pancreas development
Authors: Osipovich Anna B. , Dudek Karrie D. , Greenfest-Allen Emily , Cartailler Jean-Philippe , Manduchi Elisabetta , Potter Case Leah , Choi Eunyoung , Chapman Austin G. , Clayton Hannah W. , Gu Guoqiang , Stoeckert Christian J. , Magnuson Mark A. 
Published: March 2021

ABSTRACT
To gain a deeper understanding of pancreatic β-cell development, we used iterative weighted gene correlation network analysis to calculate a gene co-expression network (GCN) from 11 temporally and genetically defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially expressed during pancreas development. Pcdhγ genes are preferentially expressed in pancreatic endoderm, Pcdhβ genes in nascent islets, and Pcdhα genes in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage, we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. Zfp800 null mice exhibited early postnatal lethality, and at E18.5 their pancreata exhibited a reduced number of pancreatic endocrine cells, alterations in exocrine cell morphology, and marked changes in expression of genes involved in protein translation, hormone secretion and developmental pathways in the pancreas. Together, our results suggest that developmentally oriented GCNs have utility for gaining new insights into gene regulation during organogenesis.
Development and Validation of a Nomogram Prognostic Model for Resected Limited-Stage Small Cell Lung Cancer Patients
Authors: Zeng Qingpeng , Li Jiagen , Tan Fengwei , Sun Nan , Mao Yousheng , Gao Yushun , Xue Qi , Gao Shugeng , Zhao Jun , He Jie 
Published: March 2021

Abstract
Background
In this study, we developed and validated nomograms for predicting the survival in surgically resected limited-stage small cell lung cancer (SCLC) patients.

Methods
The SCLC patients extracted from the Surveillance, Epidemiology, and End Results database between 2000 and 2014 were reviewed. Significant prognostic factors were identified and integrated to develop the nomogram using multivariable Cox regression. The model was then validated internally by bootstrap resampling, and externally using an independent SCLC cohort diagnosed between 2000 and 2015 at our institution. The prognostic performance was measured by the concordance index (C-index) and calibration curve.

Results
A total of 1006 resected limited-stage SCLC patients were included in the training cohort. Overall, 444 cases from our institution constituted the validation cohort. Seven prognostic factors were identified and entered into the nomogram construction. The C-indexes of this model in the training cohort were 0.723, 0.722, and 0.746 for predicting 1-, 3-, and 5-year overall survival (OS), respectively, and 0.816, 0.710, and 0.693, respectively, in the validation cohort. The calibration curve showed optimal agreement between nomogram-predicted survival and actual observed survival. Additionally, significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed. The proposed nomogram was then deployed into a website server for convenient application.

Conclusions
We developed and validated novel nomograms for individual prediction of survival for resected limited-stage SCLC patients. These models perform better than the previously widely used staging system and may offer clinicians instructions for strategy making and the design of clinical trials.
698 mothers and babies, 38 390 nappy changes: what did we learn?
Authors: Phipps Fiona MacVane , Price Alan D , Ackers-Johnson James , Cook Penny A , Clarke-Cornwell Alexandra M. , Lythgoe Jeanne 
Published: March 2021

BackgroundSeveral industry funded studies between 2001–2018 have compared the use of a single brand of baby wipes to cleansing with water and either cloth or cotton wool during nappy changes. All of these studies found that wipes were safe and effective from birth. Recommendations from these studies have included the need for brand or formula comparison but to date, no previous study has done this.AimsThe ‘Baby skin integrity comparison survey’ (BaSICS) study was designed to compare three brands of baby wipes to determine if there was any difference in the incidence of irritant diaper dermatitis (IDD or nappy rash) during the first eight weeks of life.MethodsMothers who were allocated to a single brand of nappy but divided into three baby wipe allocation groups, collected and reported survey data on infant skin integrity during one nappy change daily with the use of a user-friendly smartphone application.FindingsAll brands of wipes were acceptable to mothers and safe and effective when cleaning during nappy changes. The brand containing the fewest ingredients showed a clinically significant advantage of fewer incidents of rash than the other two brands.ConclusionThis study demonstrated that wipe formulation is a significant factor in prevention or reduction of IDD during the first eight weeks of life.
Shifting Interfaces: An Anthology of Presence, Empathy and Agency in 21st-Century Media Arts, Hava Aldouby (ed.) (2020)
Authors: Heller Lynne 
Published: March 2021

Review of: Shifting Interfaces: An Anthology of Presence, Empathy and Agency in 21st-Century Media Arts, Hava Aldouby (ed.) (2020)
Leuven: Leuven University Press, 332 pp.,
ISBN 978-9-46270-225-7, p/bk, $69.50
Antimicrobial and antioxidant activities of Cinnamomum cassia essential oil and its application in food preservation
Authors: Kačániová Miroslava , Galovičová Lucia , Valková Veronika , Tvrdá Eva , Terentjeva Margarita , Žiarovská Jana , Kunová Simona , Savitskaya Tatsiana , Grinshpan Dmitrij , Štefániková Jana , Felsöciová Soňa , Vukovic Nenad , Kowalczewski Przemysław Łukasz 
Published: March 2021

Abstract
This study was designed to investigate chemical and antioxidant properties, as well as the antimicrobial and antibiofilm behaviour of Cinnamomum cassia essential oil (CCEO). MALDI-TOF MS Biotyper mass spectrometry was applied to evaluate the biofilms of Stenotrophonomonas maltophilia and Bacillus subtilis, while the antibiofilm ability of CCEO was assessed on wooden and glass surfaces. The antimicrobial activity by disc diffusion method, microdilution method, and vapour phase for two biofilm-producing bacteria and three Penicillium spp. were used. Antimicrobial and antibiofilm properties were assessed using the agar microdilution protocol. The vapour phase of Penicillium citrinum, P. crustosum, P. expansum, S. maltophilia, and B. subtilis on bread, carrot, potato, sweet potato, and apple in situ was studied. Specific molecular variations related to the biofilm formation and genetic analogies were evaluated with MSP spectra dendrograms of S. maltophilia and B. subtilis profiles were grown on different days. The results of disc diffusion and broth diffusion methods showed that CCEO was strongly effective against all tested microorganisms and the vapour phase method was effective and active against all Penicillium spp., but not strongly effective against bacteria in food preservation of food matrices.
Mixed methods to assess the use of rare illicit psychoactive substances: a case study
Authors: Janssen Eric , Vuolo Mike , Gérome Clément , Cadet-Taïrou Agnès 
Published: March 2021

Abstract
This article presents original mixed method research to describe the use of rare illicit psychoactive substances, with special emphasis on crack cocaine in France. We first introduce a unique monitoring system committed to the observation of hard-to-reach populations. Qualitative findings rely, among others, on perennial ethnographic studies and field professionals’ knowledge to provide guidance to estimate the number of crack cocaine users. We then rely on a set of multilevel capture-recapture estimators, a statistical procedure to indirectly estimate the size of elusive populations. Since prior field evidence suggests an increasing diversity in crack cocaine users’ profiles, we provide a measure of heterogeneity to assess which estimator better fits the data. The calculated estimates are then critically reviewed and debated in light of the previously gathered information. Our results uncover both individual and institutional heterogeneity and suggest that the spread of crack cocaine in France initiated earlier than originally thought. Our case study underlines the need for field-driven assessments to put quantitative results into perspective, a necessary step to tailor efficient health policy responses.
Testing and evaluation of cold-start emissions from a gasoline engine in RDE test at two different ambient temperatures
Authors: Pielecha Jacek , Skobiej Kinga , Kurtyka Karolina 
Published: March 2021

Abstract
In order to better reflect the actual ecological performance of vehicles in traffic conditions, both the emission standards and the applied emission tests are being developed, for example by considering exhaust emissions for a cold engine start. This article presents the research results on the impact of ambient temperature during the cold start of a gasoline engine in road emission tests. The Real Driving Emissions (RDE) tests apply to passenger cars that meet the Euro 6 emissions norm and they are complementary to their type approval tests. A portable emissions measurement system was used to record the engine and vehicle operating parameters, as well as to measure the exhaust emissions during tests. This allowed for parameters such as engine load, engine speed and vehicle speed to be monitored. The cold start conditions for two different temperatures (8°C and 25°C) were compared in detail. Moreover, the engine operating parameters, exhaust concentration values and road emissions for the 300 s time interval, were compared. The summary of the article presents the share of a passenger car’s cold start phase for each exhaust compound in the urban part of the test and in the entire Real Driving Emissions test depending on the ambient temperature.