bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 386: Evaluation of CPa9-HNE - a peripheral biomarker based on neutrophil extracellular traps (NETs) - for predicting outcome in patients with metastatic melanoma treated with anti-PD-1 therapy
Authors: Jensen Christina , Kverneland Anders , Donia Marco , Mortensen Joachim H. , Karsdal Morten A. , Svane Inge Marie , Willumsen Nicholas 
Published: July 2021

Abstract
Background:
Peripheral biomarkers associated with response and resistance to anti-PD-1 therapy in metastatic melanoma patients represent an unmet medical need. High neutrophil activity is associated with immune checkpoint inhibitor failure, amongst others due to release of neutrophil extracellular traps (NETs) that have been shown to protect tumor cells against cytotoxic attacks. Human neutrophil elastase (HNE) and calprotectin are the major NETs constituents. We hypothesized that HNE mediated degradation of calprotectin (CPa9-HNE), when measured in serum, has peripheral biomarker potential in metastatic melanoma patients treated with anti-PD-1 therapy.
Methods:
A monoclonal antibody was raised against a specific HNE mediated degradation fragment of calprotectin (CPa9-HNE) and used to develop an ELISA for quantifying CPa9-HNE in serum. CPa9-HNE was then measured in pre-treatment serum from metastatic melanoma patients treated with anti-PD-1 therapy (pembrolizumab) (n=35). The biomarker levels were associated with progression-free survival (PFS) and overall survival (OS) by univariate and multivariate Cox regression analyses adjusting for PDL1 expression (≥1%), lactate dehydrogenase (LDH), BRAF mutational status, and c-reactive protein (CRP).
Results:
High pre-treatment CPa9-HNE levels predicted worse PFS (HR=3.32, 95%CI=1.25-8.82, p=0.016) and OS (HR=11.31, 95%CI=2.27-56.33, p=0.003) when compared to low CPa9-HNE levels by univariate Cox regression. By multivariate Cox regression, high CPa9-HNE was found to be independently predictive of poor PFS (HR=8.22, 95%CI=1.30-52.14, p=0.025) and OS (HR=76.87, 95%CI=4.73-1248.57, p=0.002) when adjusted for PDL1 expression, LDH, BRAF mutations, and CRP.
Conclusions:
A non-invasive biomarker of HNE mediated degradation of calprotectin (CPa9-HNE) was associated with poor PFS and OS in metastatic melanoma patients treated with anti-PD-1 therapy. These findings support a link between neutrophil activity/NETs and response to anti-PD-1 and indicate promising non-invasive biomarker potential to stratify melanoma patients for anti-PD-1 therapy in future clinical studies.
Citation Format: Christina Jensen, Anders Kverneland, Marco Donia, Joachim H. Mortensen, Morten A. Karsdal, Inge Marie Svane, Nicholas Willumsen. Evaluation of CPa9-HNE - a peripheral biomarker based on neutrophil extracellular traps (NETs) - for predicting outcome in patients with metastatic melanoma treated with anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 386.
Abstract 395: Prediction of genomic based drug sensitivity signatures to enable optimal drug positioning
Authors: Gilvary Coryandar , Elemento Olivier , Madhukar Neel 
Published: July 2021

Abstract
Cancer by nature, is a heterogeneous disease, which can lead to highly variable patient responses for targeted therapies - even within the same clinically defined cancer type or subtype. Identifying drug sensitivity biomarkers, patient specific traits that are highly correlated with positive response, has proven to be an effective strategy to identify positioning opportunities and selecting patients. Here, we describe our biomarker identification workflow which identifies drug specific genomic sensitivity signatures, a collection of genomic aberrations that are found to be predictive of patient response, which can be used for patient selection as well as understanding a compound's mechanism of action. Using available drug efficacy data (in vitro or in vivo results) with paired baseline genomics data, we build diverse models to predict sample sensitivity to a drug. For every model, we train and measure the performance and how each genomic aberration contributes to model performance, those that do not sufficiently increase predictability are removed. This process is repeated, with each new model training on a smaller subset of genomic aberrations, until we have the minimum number of genomic aberrations needed to reach peak predictive performance. The resulting set of genomic aberrations make up a genomic sensitivity signature. Instead of using one type of algorithm to build these models, we train three distinct model types: linear, decision tree and custom kernel based. The multiple model architecture allows us to model the unique underlying biological mechanism of a compound's efficacy, such as synthetic lethal relationships or resistant pathway deactivation, ultimately giving us a collection of robust biomarker signatures. In addition to mechanistic understanding, clinical feasibility was a top priority. Therefore, our workflow architecture has been tested and validated to incorporate mutation, copy number alteration and/or gene expression based biomarkers either in combination or alone. This flexibility lowers the data required to use our workflow, making it more widely available to investigational drugs. Our identification of genomic sensitivity signatures can then be used for clinical patient selection or positioning a compound for a clinically defined cancer type, based on the prevalence of the predicted signature. Overall, this workflow is a powerful approach identifying diverse, mechanism based drug sensitivity signatures that can enable identifying the right patient for a therapy of interest.
Citation Format: Coryandar Gilvary, Olivier Elemento, Neel Madhukar. Prediction of genomic based drug sensitivity signatures to enable optimal drug positioning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 395.
Abstract 40: Targeting SOX10-deficient cells to reduce resistance to targeted therapy in melanoma
Authors: Capparelli Claudia , Purwin Timothy J. , Tiago Manoela , Wilski Nicole , Pomante Danielle , Glasheen McKenna , Rosenbaum Sheera , Nguyen Mai Q. , Cai Weijia , Zheng Richard , Kumar Gaurav , Chervoneva Inna , Shimada Ayako , Snook Adam E. , Fortina Paolo , Xu Xiaowei , Hookim Kim , Cukierman Edna , Davies Michael A. , Herlyn Meenhard , Aplin Andrew E. 
Published: July 2021

Abstract
Intratumoral heterogeneity and cellular plasticity enable tumors to alter phenotypes and adapt to foreign microenvironments and resist targeted inhibitors. While the ability to switch between phenotypic states has been broadly characterized, the key mechanisms that underlie tumor plasticity remain poorly understood. We studied the neural crest lineage transcription factor, SOX10, in the context of cutaneous melanoma and resistance to targeted therapies. SOX10 is heterogeneously expressed in melanoma samples. Using bio-informatics as well as in vivo and 3D in vitro melanoma models, SOX10 loss was sufficient to induce an invasive but slow proliferating phenotype in vitro and in vivo that was associated with expression of a mesenchymal gene set. Interestingly, while SOX10 knockout initially induced a targeted inhibitor tolerant state, longer exposure of co-mixed populations of SOX10 proficient and SOX10 deficient to targeted therapy drives the clonal selection of SOX10 knockout cells. Furthermore, cell lines generated from xenograft tumors that have acquired resistance to either vemurafenib, paradox-breaking BRAFi or the combination of BRAFi + MEKi showed dramatically reduced SOX10 expression compared to their parental counterparts. Altogether these data suggest that acquired resistant clones may arise from drug tolerant persister cells. As a strategy to selectively target this invasive, drug-tolerant SOX10-deficient sub-population, we screened a drug compound library and identified a class of cIAP1/2 inhibitors to be synthetically lethal for SOX10-deficient cells. Our preliminary data suggest that birinapant can delay or prevent resistance to BRAFi/MEKi in vivo. Together, these data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma and enables tumor adaptation to altered microenvironments and drug treatments which could be targeted using cIAP1/2 inhibitors.
Citation Format: Claudia Capparelli, Timothy J. Purwin, Manoela Tiago, Nicole Wilski, Danielle Pomante, McKenna Glasheen, Sheera Rosenbaum, Mai Q. Nguyen, Weijia Cai, Richard Zheng, Gaurav Kumar, Inna Chervoneva, Ayako Shimada, Adam E. Snook, Paolo Fortina, Xiaowei Xu, Kim Hookim, Edna Cukierman, Michael A. Davies, Meenhard Herlyn, Andrew E. Aplin. Targeting SOX10-deficient cells to reduce resistance to targeted therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 40.
Abstract 434: Characterizing viral mRNA and immuno-protein expression in head and neck squamous cell carcinoma using a novel automated RNAscope™/Polaris™ integrated assay
Authors: Pollan Sara , Hanifi Arezoo , Nagy Mate , Stavrou Nicholas , Parnell Erinn , Gozo Maricel , Attanasio Nickolas , William Josette , Au Qingyan 
Published: July 2021

Abstract
Background: Chronic viral infection can generate inflammatory microenvironments leading to neoplastic growth and cancer development. Cancer patients with chronic viral infection have been shown to exhibit worse outcomes compared to non-infected individuals. One such cohort, head and neck squamous cell carcinoma (HNSCC) patients infected with chronic human cytomegalovirus (CMV), have increased risk of death when receiving radiotherapy or radiochemotherapy. This is clinically significant as HNSCC already carries a high mortality rate and low response to surgery and chemotherapeutic treatment. The ability to detect and localize viral infection and immune response in the same patient tissues has been historically under-developed and may assist in stratifying patients for therapeutic intervention.
Methods: Immune infiltrate to tumor in CMV infected and non-infected samples was assessed in HNSCC patient tissue using RNAscope in-situ hybridization (ISH) probe to detect CMV mRNA and Vectra® Polaris™ automated multiplex protein detection of CD8, PD-L1, CD68 and panCK with OPAL dyes.
Results: We developed a novel automated RNAscope™/Vectra® Polaris™ integrated multiplex immunofluorescence (IF) assay with OPAL detection and quantification of signal using Indica HALO® algorithms. The results include quantitative and reproducible RNAscope fluorescent ISH counting, cell-by-cell expression profiles, multiplex protein quantification and whole-slide image analysis.
Conclusion: NeoGenomics Laboratories RNAscope™/Polaris™ integrated assay detects and quantifies CMV viral infection and protein expression of PD-L1 positive and negative cytotoxic T cells and macrophages within and adjacent to HNSCC tumor regions.
Citation Format: Sara Pollan, Arezoo Hanifi, Mate Nagy, Nicholas Stavrou, Erinn Parnell, Maricel Gozo, Nickolas Attanasio, Josette William, Qingyan Au. Characterizing viral mRNA and immuno-protein expression in head and neck squamous cell carcinoma using a novel automated RNAscope™/Polaris™ integrated assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 434.
Abstract 442: Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189
Authors: Gadgeel Shirish , Grey Jhanelle , Rizzo Maria Teresa , Peterson Patrick , Kim Jongseok , Rodríguez-Abreu Delvys 
Published: July 2021

Abstract
Background: Pemetrexed (pem) and platinum (plat) plus pembrolizumab (pembro) showed clinical improvement in metastatic nonsquamous (NSQ) non-small-cell lung cancer (NSCLC). The aim of this analysis was to assess the clinical benefit of pem+plat+pembro in patients by tumor burden at baseline.
Methods: The intention-to-treat population was analysed. Patients were randomized pem+plat+pembro (n=410) or pem+plat+placebo (n=206). The data cut-off date was May 20, 2019. OS, PFS, PFS-2, and ORR were evaluated by Kaplan-Meier and univariate Cox methods within subgroups identified by extent of distant metastasis (M1a vs. M1b), median number (≤3 vs. &gt;3) of organ systems with lesions, and severity score of patient-reported symptoms (below median vs. above median) at baseline. These subgroup analyses were also replicated within PD-L1 TPS subgroups (&lt;1%, 1-49%, ≥50%).
Results: A consistent benefit in OS, PFS, PFS-2 and ORR was observed in the pem+plat+pembro treatment arm, compared to the pem+plat+placebo arm, irrespective of staging (M1a vs. M1b), number (≤ 3 vs. 3) of organ systems with lesions and severity of patient-reported symptoms (Table 1). Results by PD-L1 expression in the subgroups were generally consistent regardless of the level of expression.
Conclusions: Pem+plat+pembro demonstrated consistent clinical benefit across all subgroups analysed regardless of baseline tumor burden. These results continue to support pem+plat+pembro as a standard of care in metastatic NSQ-NSCLC.
TABLE 1.OS, PFS, PFS-2, and ORR in subgroups by tumor burden at baselineTreatment armsNaOSPFSPFS-2ORRHRHRHROdds ratioM1aPembro1230.540.480.572.66Placebo53M1bPembro2850.580.510.504.21Placebo152≤ 3b organ systems with lesionsPembro2350.490.410.436.00Placebo118&gt; 3b organ systems with lesionsPembro1750.670.590.601.80Placebo88≤ medianc severity score of symptomsPembro1700.510.490.432.72Placebo82&gt; medianc severity score of symptomsPembro1870.600.480.554.04Placebo97a.There were 3 patients with missing data for M1a and M1bb.Median number of organ systems with lesions was 3. Lesions include the primary tumorc.Median score = 122.2, based on six questions from the patient-reported LC-13 instrument
Citation Format: Shirish Gadgeel, Jhanelle Grey, Maria Teresa Rizzo, Patrick Peterson, Jongseok Kim, Delvys Rodríguez-Abreu. Pemetrexed and platinum plus pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer by tumor burden at baseline: A post-hoc efficacy analysis of KEYNOTE-189 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 442.
Abstract 456: Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma
Authors: Yekula Anudeep , Kitchen Robert R. , Chakrabortty Sudipto K. , Carter Bob S. , Skog Johan , Balaj Leonora 
Published: July 2021

Abstract
Introduction
Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. This ability to non-invasively profile tumors, opens new avenues for diagnosis, patient stratification to novel therapies, as well as monitoring. Here, we provide evidence of extracellular vesicle EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM in a multi-armed, multi-institutional clinical trial (NCT01112527).
Methods
We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment.
Results
Firstly, our novel RNASeq workflow on EV derived long RNA allowed the detection of thousands of protein coding genes, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers of GBM.
Secondly, we observed a differential expression profile is serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer including gliogenesis, epithelial to mesenchymal transition, invasion, regulation of stemness, apoptosis and cell cycle regulation, immune regulation and metabolic remodeling.
Thirdly, we observed a differential expression profile is serum EV RNA of responders compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification.
Finally, we also observed a differential expression profile is serum EV RNA of responders compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy.
Conclusion
This study is unique because it represents the first longitudinal profiling of the EV RNA in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring.
Citation Format: Anudeep Yekula, Robert R. Kitchen, Sudipto K. Chakrabortty, Bob S. Carter, Johan Skog, Leonora Balaj. Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 456.
Abstract 467: Detecting ALK rearrangement by RT-PCR: A superior approach to next generation sequencing
Authors: Kuang Yukun , Xu Peihang , Wang Jiyu , Zheng Yifan , Sun Xue , Li Zimu , Gan RunJing , Li Huixia , Guo Yubiao , Zhu Guanshan , Zhu Changbin , Ke Zunfu , Tang Kejing 
Published: July 2021

Abstract
Background: Precisely detecting anaplastic lymphoma kinase (ALK) rearrangement ensures ideal efficacy of ALK targeted tyrosine kinase inhibitors (ALK-TKIs). Next generation sequencing (NGS) has been widely used in clinics, while, numbers of studies indicated NGS would yield false negative outcome, especially for fusion analysis. Instead, more fusions can be detected by RT-PCR at transcription level. This study aims to compare the capacity of RT-PCR and NGS approach to detect ALK rearrangement in Chinese non-small-cell lung cancer (NSCLC) patients.
Methods: Formalin-fixed paraffin-embedded (FFPE) tissues from 153 patients pathologically diagnosed as NSCLC with eligible ALK status given by previous NGS testing (29 patients were ALK positive and 124 patients were ALK negative) were collected from November 2017 to October 2019. RT-PCR were applied to detect ALK rearrangements in both groups. For samples with discordant result of ALK status, fluorescence in situ hybridization (FISH) or Sanger's sequencing were used for validation.
Results: One hundred and twenty-four samples (26 of 30 ALK positive samples; 98 of 124 ALK negative samples) were successfully subjected to RT-PCR. Five of 98 ALK negative samples given by NGS test were re-defined as ALK positive by RT-PCR. Meanwhile, in 26 ALK positive samples, RT-
PCR yielded acceptable result with 96.15% of concordance rate. Only one NGS-defined ALK positive sample was uncovered by RT-PCR due to a rare ALK rearrangement. Four of 6 RT-PCR defined ALK positive cases (3 RT-PCR positive and 1 NGS positive) were validated by either FISH or sanger's sequencing, which resulted positive result.
Conclusions: RT-PCR displays reliable and superior capacity to detect ALK fusion in NSCLC patients.
Citation Format: Yukun Kuang, Peihang Xu, Jiyu Wang, Yifan Zheng, Xue Sun, Zimu Li, RunJing Gan, Huixia Li, Yubiao Guo, Guanshan Zhu, Changbin Zhu, Zunfu Ke, Kejing Tang. Detecting ALK rearrangement by RT-PCR: A superior approach to next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 467.
Abstract 475: Improving liposarcoma diagnosis through cross-flow microfiltration
Authors: Casadei Lucia , Sarchet Patricia , Choudhury Adarsh , Prakash Shaurya , Pollock Raphael 
Published: July 2021

Abstract
Introduction: Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late and patients typically respondpoorly to treatments bringing to an overall survival rate of only 10% at 10 years. Prognosis isenhanced by early detection of recurrent lesions, but current diagnostic methods rely on invasivetissue biopsies combined with whole or part-body imaging. These diagnostic and prognosticchallenges prompted us to explore the use of circulating biomolecules as potential biomarkersaccessible through bodily fluids. Extracellular Vesicles (EVs) are membrane vesicles containingproteins and nucleic acids that circulate in the blood, so they are an emerging class of easilyaccessible blood biomarkers. We recently identified extracellular vesicle EV-MDM2 as liquidbiopsy biomarker for disease identification in DDLPS. Unfortunately, due to these challenges forisolation and capture of EVs, despite the potential diagnostic and prognostic utility, the practicalrelevance of using EVs for routine analysis remains limited.
Methods: A microfluidic device was fabricated via standard soft lithography in PDMS(polydimethylsiloxane). A 5 x 5 mm2 nanocapillary array membrane (nominal capillary diameterof 0.2 µm) was sandwiched between two microchannels for a vertically aligned configuration withan injection and separation channel (each 500 µm wide and 150 µm high) perpendicular to eachother. The separation channel surface was functionalized with the anti-CD63 antibody forcapturing EVs.
Results: We present here a facile approach to fabricate and operate a micro-nanofluidic device that usescross-flow filtration to isolate and capture liposarcoma derived EVs. Our methodology integratesthe unit operations of size based separation with immunoaffinity-based capture of extracellularvesicles in the same device. The eluted media collected showed ~84% extracellular vesiclerecovery from the liposarcoma cell conditioned media and ~38% extracellular vesicle recoveryfrom dedifferentiated liposarcoma patient serum when compared to extracellular vesicle isolationand subsequent quantification by ultracentrifugation. The results reported here also show a five-fold increase in amount of critical liposarcoma relevant extracellular vesicle cargo obtained in30 minutes presenting a significant advance over existing state-of-art.
Conclusion: In conclusion we developed a cross-flow filtration micro-nanofluidic device for isolation, selectivecapture and release of liposarcoma EVs.
Citation Format: Lucia Casadei, Patricia Sarchet, Adarsh Choudhury, Shaurya Prakash, Raphael Pollock. Improving liposarcoma diagnosis through cross-flow microfiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 475.