bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying small cell lung cancer resistance mechanisms to cytotoxic T cells in vitro using whole genome CRISPR screening.
Authors: Hiatt Joseph , MacPherson David 
Published: March 2020

e20075 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine neoplasm associated with high tumor mutation burden (TMB), a paucity of compelling therapeutic options, and very poor survival. In comparison to other malignancies with high TMB, SCLC patients tend to experience lower response rates and shorter response durations with immune checkpoint blockade (ICB) targeting the PD-1 and/or CTLA-4 axes, and chemotherapy with ICB in first line does not exhibit the dramatic synergy seen in non-small cell lung cancer. To identify additional immunosuppressive mechanisms that could serve as novel biomarkers and therapeutic targets in SCLC, we adapted a recently described method to screen for genes that alter the sensitivity of cancer cells to killing by cytotoxic CD8+ T cells. Methods: We introduced Cas9 nuclease and a genome-wide gene inactivation library of ~80,000 single guide RNA (sgRNA) templates into a cell line derived from a genetically engineered murine model of SCLC (mSCLC). In parallel, we isolated and stimulated CD8+ T cells from the OT-I transgenic mouse, which express a rearranged T cell receptor with very high avidity for the ovalbumin (OVA) SIINFEKL peptide presented on H2-K(b) class I MHC. mSCLC cells were loaded with OVA peptide or vehicle and co-cultured with T cells for 24 hours. We collected surviving cells, isolated DNA, and used next-generation DNA sequencing to tabulate the relative representation of sgRNAs in each experimental condition. From these data, we inferred which gene knockouts were protective from, or sensitizing to, killing by CD8+ T cells. Results: We observed expected mediators, including resistance via knockout of antigen presentation machinery and sensitization via knockout of pro-survival pathways ( e.g. NF-kB), and unexpected hits spanning diverse cellular functions. Conclusions: Genome-wide screening for mediators of in vitro killing by CD8+ T cells in a murine model of SCLC is feasible and reveals that both expected and novel pathways may contribute to resistance to immunotherapy in SCLC. Future studies are directed at validating these hits in vitro and in vivo, incorporating new complex gene perturbation libraries, and scaling to additional cell lines.
Precision medicine and actionable alterations in lung cancer.
Authors: Mambetsariev Isa , Nadaf Sorena , Wang Yingyu , Chen Chen , Hewelt Blake , Pharaon Rebecca , Massarelli Erminia , Koczywas Marianna , Reckamp Karen L. , Salgia Ravi 
Published: March 2020

e20707 Background: In recent years, healthcare centers have become more reliant on the advent of new technology, testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians, researchers, and the medical community. This aggregate of information stands to be a powerful tool that can enable one to perform highly complex investigations more easily, as well as aid physicians in their efforts to provide personalized medicine to patients. However, in order to take advantage of vital clinical and research data, we must initially make an effort to create an effective infrastructure for the collection, storage, utilization, and protection of this information with uniquely designed disease-specific registries that have adequate informatics support to allow for the collection of a large number of patients. Methods: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. Results: Of the 415 patients in the analysis, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The frequency of the most commonly occurring oncogenes was 50% EGFR (n = 207/415), 28% KRAS (n = 97/352), and 7% ALK rearrangement (n = 28/377), while the most commonly occurring tumor suppressor genes consisted of TP53 (n = 140/283 [49%]), LRP1B (n = 63/228 [28%]), and STK11 (n = 39/278 [14%]). The most common actionable alterations were identified in EGFR L858R/exon 19 deletion (n = 177/415 [42.7%]), ALK rearrangement (n = 28/377 [7.4%]), ROS1 rearrangement (n = 3/257 [1.2%]), BRAF V600E (n = 7/288 [2.4%]) and MET exon 14 splice site/deletion (n = 7/287 [2.4%]). While there were no median OS differences in patients who were tested under a broad-panel vs small-panel (33.4 months vs 33.5 months; 95% CI; P = 0.36), there was a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 patients who were wild-type with a median OS of 26.0 months (95% CI; P < 0.001). In addition, we identified an unprecedented number of patients with actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively. Conclusions: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.
Effect of a multi-disciplinary approach and incorporation of reflex testing on genomic profiling of non-squamous lung cancer in a community oncology practice.
Authors: Gupta Niraj K. , Toney Brent , Uprety Sajeev , Mastrodicasa Mark , Ascioti Anthony , Nuthakki Vijay , Leagre Christopher A. , Mahidhara Raja , Freeman Richard K , Jhajria Sunil , Schroeder Ryan , Mintz Ed , Schmidt Kristen , Tumati Vas , Liebross Robert H. 
Published: March 2020

e20719 Background: Genomic profiling of advanced non-squamous lung cancer is integral for appropriate management. Appropriate testing and timeliness in getting the results often pose a challenge in a community setting. We share our experience in a community setting and the importance of an integrated approach to improve outcomes. Methods: Retrospective review of the charts of patients with stage- III-B/IV was conducted to gather data. Effect of Multi-disciplinary meetings to improving coordination among treating physicians and Incorporation of reflex testing for complete mutational profiling on diagnosis was studied. Results: Between 04/2016 and 10/2018, 127 patients charts were reviewed. 83% were stage-IV and 17% stage-III-B. Males (61%), Females (49%). Median age was 62 yrs. 76% had smoking history.There were 53% core biopsies, 42% FNAs and 5% resections. Mutational profiling panel was based on the NCCN guidelines. Adequate specimen for complete profiling was available in 111/127 (87%) of the patients. Two/16 (12%) of pts with in-adequate sample had a repeat biopsy and 12/16 ( 75%) had liquid biopsies done. Remaining 2 pts didnot have further w/u due to declining PS. Complete mutational profile (EGFR/ALK/ROS-1/MET/RET/BRAF/PDL-1) was available in 100% of pts. after re-biopsy/liquid bx. Incorporation of reflex testing decreased the reporting time from an average of 11.6 days to 6.9 days. The results of mutational profiling were available in 94% of pts. before starting the treatment. Prevalence of mutations were, EGFR:14%, ALk:3%, BRAF:1%, MET:0%, RET:1%, ROS-1:2%. Conclusions: Multi-disciplinary integrated approach and reflex testing upon diagnosis is essential for appropriate and timely genomic profiling of locally advanced/ metastatic non-squamous lung cancer patients to deliver appropriate treatment in a community setting.
Real-world (rw) clinical outcomes for advanced/metastatic non-small cell lung cancer (aNSCLC) patients (pts) treated with second line (2L) ramucirumab plus docetaxel (R+D) post frontline (1L) platinum based chemotherapy plus immune checkpoint inhibitors (Pt + ICI).
Authors: Clarke Jeffrey Melson , Mathur Raina , Molife Cliff , Batus Marta , Stefaniak Victoria Jennifer , Winfree Katherine B. , Baxi Shrujal , Cui Zhanglin Lin , Lenis David , Bonomi Philip D. 
Published: March 2020

e20727 Background: R+D is approved for use in pts with aNSCLC after Pt chemotherapy. With recent approvals, ICI can now be added to Pt chemotherapy (Pt + ICI) in 1L. This retrospective observational study provides an exploratory view of baseline characteristics and rw clinical effectiveness outcomes for pts receiving 2L R+D post 1L Pt + ICI. Methods: All adult pts treated with 2L R+D after 1L Pt + ICI therapy between 03/01/2015 and 06/30/2018, with ≥ 3 months follow up, were selected from the Flatiron Health EHR-derived de-identified database (n = 15). Rw clinical endpoints during R+D therapy included rw objective response rate (rwORR), rw disease control rate (rwDCR), rw best response, as well as Kaplan-Meier estimates of rw time to first response & rw duration of response. Results: Median age was 62 years, 10 pts (66.6%) were aged < 65 years, 11 (73.3%) were men, 3 (20.0%) had no history of smoking, 14 (93.3%) had non-squamous histology, 4 (26.7%) were EGFR positive, 3 (20.0%) were KRAS positive and 6 (85.7%) were PD-L1 negative. Of the 8 pts with a documented rw tumor response assessment, 3 (37.5%) had partial response (PR), 3 (37.5%) had stable disease (SD), & 2 (25.0%) had progressive disease as their rw best response. The rwORR (PR or complete response [CR]) & rwDCR (PR, CR, or SD) were 37.5% and 75.0%, respectively. Among responding pts, median time to first response was 2.2 months (95% CI, 1.3 - not reached [NR]) & median duration of response was 2.3 months (95% CI, 1.5 - NR). Patient numbers were too small (n = 15) and duration of follow-up was too short (3.4 months [IQR, 0.7 - 5.4]) to make robust estimation of overall survival or rw progression free survival. Conclusions: Data from this small patient cohort in US community practice are not conclusive and should be considered exploratory, but do show high rates of rw objective response and rw disease control rates during 2L R+D following 1L Pt + ICI. Data with larger sample sizes and additional follow-up are needed to better understand outcomes of R+D following the addition of ICI to 1L Pt chemotherapy regimens.
MET second-site mutations in EGFR-mutant, MET-amplified non-small cell lung cancer after resistance to combinatorial targeted therapy.
Authors: Cheng Jia-Tao , Yang Jinji , Wu Yilong 
Published: March 2020

e20730 Background: MET second-site mutations were previously reported in a few cases of MET-amplified or exon 14-mutant advanced non-small-cell lung cancer (NSCLC) treated with MET inhibitors. However, both the frequency of MET second-site mutations and clinical outcome of patients with such genetic alterations have not been investigated, particularly in EGFR-mutant, MET-amplified advanced NSCLC treated with combinatorial targeted therapy. Methods: Retrospectively, from November 2016 to January 2019, 22 patients with EGFR-mutant, MET-amplified advanced NSCLC had sufficient tumor samples after resistance to a combinatorial therapy with both EGFR and MET inhibitors. All tissue samples were detected using Next-generation sequencing (NGS). The progression-free survival (PFS) was calculated the start of subsequent treatment to progressive disease or death from any cause. The overall survival (OS) was calculated from the start of subsequent treatment to death from any cause. Last follow-up was on January 31, 2019. Results: Five kinds of MET second-site mutations were found in 7 patients: D1246N D1228N, D1228H, D1231Y and Y1230H. The frequency of MET second-site mutations was 31.8% (7/22). The median PFS and OS were 3.7 (95%CI: 1.13-6.3) months and 6.9 (95%CI: 0.2-13.7) months respectively. The ORR of EGFR TKIs plus cabozantinib for suchsecond-site mutaant patients was 50% (2/4). However, the ORR of other treatments was 0% (0/3), Two of them received single agent cabozantinib, and PFS was 0.7 and 1.7 months respectively. One had a PFS of 2.5 months with pemetrexed/carboplatin plus bevacizumab. Conclusions: MET second-site mutation might be one of the commonly-seen molecular mechanisms of acquired resistance to combinatorial targeted therapy in EGFR-mutant, MET-amplified advanced NSCLC. Patients with such mutations could respond to cabozantinib plus EGFR TKI. Further more investigations are warranted to improve the efficacy.
Evaluation of outcome and prognostic factors in paediatric extraskeletal ewings sarcoma: A single institution experience.
Authors: Srinivasalu Vijay Kumar , Sankaran Hari , Subramaniam Narayana , Philip Arun , Jose Wesley Mannirathil , Keechilat Pavithran 
Published: March 2020

e21507 Background: Ewing's sarcoma (ES) represent the most frequent small and round cell bone tumors of childhood and adolescence. Data on extraskeletal ewings sarcoma (EES) with uniform chemotherapy protocol are very minimal. We aimed to assess this aspect in our patients and identify prognostic factors in patients with extraskeletal ewings sarcoma. Methods: A retrospective analysis of data was done between January 2005 and January 2016. These paediatric EES patients who received chemotherapy with VAC-IE regimen were evaluated for their response, overall survival (OS) and Event free survival (EFS). The prognostic factors which influenced their overall survival were also analysed. Results: Fourty one paediatric EES patients were diagnosed at our institute out of which 31 patients received treatment at our hospital. 25.8% (8) were metastatic at presentation. The mean age was 12.37 years (1-18 years) with a predominant female preponderance 54.8%. The commonest site at presentation was presacral mass (7) and mass in the brain parenchyma (8). Rare sites of presentation as a nasal mass and parotid mass was seen in one patients each. 78% received chemotherapy with VAC-IE regimen. The ORR was 71% (8 CR + 9 PR). Toxicity was grade III neutropenia in 5 (20.8%). 8 patients received local RT. The 3 year OS and EFS in the localized EES were 55% and 39% and in metastatic EES were 35% and 24% respectively. Low hemoglobin (P = 0.05) and high LDH (P = 0.01) predicted inferior OS for the entire EES cohort on multivariate analysis. Conclusions: High LDH and low hemoglobin is associated with poor OS for patients with EES ewings sarcoma. VAC-IE is a very effective and a safe chemotherapy regimen and should be considered in patients with extraskeletal ewings sarcoma.
Shared dysregulation of long non-coding RNA and developmental gene networks in histone H3 K27M gliomas and PF-A ependymomas.
Authors: Sanders Lauren , Cheney Allison , Beale Holly , Kephart Ellen , Bjork Isabel , Pfeil Jacob Joseph , Salama Sofie R. , Haussler David , Morozova Olena 
Published: March 2020

e21523 Background: Diffuse pediatric gliomas harboring a Histone-H3 K27M mutation are more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue1. As a result, these tumors show global aberrant gene expression, resulting in a stem-like proliferative cell population2. Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences3. Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth4,5. Methods: We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development6, and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of lncRNA networks responsible for maintaining normal differentiation programs. Results: Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. Conclusions: We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types. References: 1. Chan KM, Fang D, Gan H, et al. Genes Dev. 2013;27(9):985-90; 2. Filbin MG, Tirosh I, Hovestadt V, et al. Science. 2018;360(6386):331-5; 3. Witt H, Mack SC, Ryzhova M, et al. Cancer cell. 2011;20(2):143-57; 4. Bayliss J, Mukherjee P, Lu C, et al. Sci. Transl. Med. 2016;8(366):366ra161; 5. Mack SC, Witt H, Piro RM, et al. Nature. 2014;506(7489):445; 6. Field AR, Jacobs FM, Fiddes IT, et al. bioRxiv. 2017:232553.
Developmental differences in health-related quality of life (HRQL) in adolescent and young adult (AYA) survivors of childhood cancer.
Authors: Becktell Kerri , Phelan Rachel , Schmidt Debra , Anderson Lynnette , Nichols Julie , Simpson Pippa , Bingen Kristin 
Published: March 2020

e21524 Background: AYAs experience many distinct periods of developmental transition within this life stage. AYA survivors of childhood cancer are at risk for chronic physical and psychosocial health conditions due to treatment-related exposures. Few studies have evaluated HRQL differences that may exist among developmental subgroups of AYA cancer survivors. This study examined HRQL differences across AYA developmental subgroups (early teens 12-14 years; late teens 15-17; emerging adults 18-24; young adults 25-39) of long term childhood cancer survivors. Methods: Cancer survivors ages 12-39 years who were seen in a long term follow up clinic at time of survey completion (as part of larger HRQL study) and completed therapy ≥2 years ago were included. HRQL was assessed using PedsQL (< 18) and FACT-G (> 18) measures. Demographic and treatment data were obtained from EMR. Analyses compared HRQL measure scores among AYA age subgroups and investigated predictors of HRQL outcomes. Results: A total of 155 patients were included in analysis. Mean age at survey completion was 17.9 [range 12-33] years. PedsQL school functioning was significantly lower for 15-17 year-old compared to 12-14 year-old survivors (M = 77.60, p = 0.01). There were no differences between 18-24 and 25-39 year-old survivors on the FACT-G. PedsQL school functioning was significantly lower for survivors (< 18) compared to normative data (p = 0.004). FACT-G scores for survivors were significantly higher compared to population norms in all domains (p≤0.001) except emotional well-being. Regression CART analysis indicated survivors who were ≤15 years-old and had not relapsed and survivors who were > 15 years old and had ≥2 late effects had lower PedsQL scores. Survivors who were ≥21 years-old had lower FACT-G scores compared to < 21 years. Survivors who were < 21 years-old, > 7 years-old at diagnosis, and > 6 years from end of treatment had lower FACT-G scores. Conclusions: Adolescent survivors may be at risk for school problems years after cancer treatment. Young adult survivors may be at greater risk of poor HRQL. This study highlights potential developmental differences in HRQL predictors and outcomes in long term AYA cancer survivors.
Tumor control with palliative external beam radiation therapy (EBRT) in advanced and unresectable osteosarcoma (OS) progressing after standard treatment.
Authors: Tolomeo Francesco , Gatti Marco , D'Ambrosio Lorenzo , Rampino Monica , Boglione Antonella , Merlini Alessandra , Manessi Giulia , Miano Sara , Salatino Antonia , Cattari Gabriella , Bertotto Ilaria , Robba Tiziana , Mussano Anna , Rossi Laura , Piana Raimondo , Comandone Alessandro , Aliberti Sandra , Aglietta Massimo , Grignani Giovanni 
Published: March 2020

e22508 Background: Advanced OS still represents an unmet medical need. Chemotherapy and targeted therapies have only limited activity in this disease. Moreover, OS is considered a radioresistant tumor at doses conventionally achieved by EBRT. We retrospectively evaluated the impact of palliative EBRT in patients (pts) with advanced OS. Methods: Main inclusion criteria: confirmed histological diagnosis of OS; EBRT for advanced/metastatic disease deemed unresectable after multidisciplinary tumor board discussion; ECOG performance status ≤3, age ≥18 years at RT start; progressive disease at site of irradiation with symptoms (e.g., pain or neurological deficit) or involving critical structures (e.g., superior vena cava compression). Endpoints: progression-free survival (PFS), PFS for RT-treated lesions (RT-PFS), best response with RT, overall survival. All survival endpoints were computed from RT start. We calculated the equivalent total dose in 2 Gy fractions (EQD2). Results: 23 pts, 15 males, median age at diagnosis 33 (17-82), median age at RT start 36 (20-83) were included. All pts had grade 3-4 OS (12 osteoblastic; 6 chondroblastic; 5 other), 7 were metastatic at diagnosis. At time of RT, median metastatic sites were 2 (1-5), 15 pts were symptomatic (11 pain, 4 neurological deficit) and were mainly heavily pretreated [median previous chemotherapies 2 (1-5), median previous surgery 1 (0-2)]. Overall, 45 lesions underwent EBRT. Median EBRT dose per lesion was 33 Gy (IQR 25 - 46.5) with a median dose per fraction of 3 Gy (IQR 3-7.5). Calculated median EQD2 was 50 Gy (IQR 36 - 88). Median PFS, RT-PFS, and overall survival were 5 (95%CI 2-9), 11 (5-15), and 12 months (8-16), respectively. Compared to systemic progression, median progression delay of irradiated lesions was 6 months (95%CI 2 - 12). In 40 lesions evaluable for dimensional response, we observed tumor shrinkage > 30% in 7 lesions, stability in 24, and progression in 9. Conclusions: EBRT might have a role in the treatment of advanced OS. In consideration of the limited activity of medical treatments, EBRT might help in disease control in the advanced setting, delaying progression especially at critical sites.
Work productivity loss in patients with tenosynovial giant cell tumors in the United States.
Authors: Lin Feng , Kwong Jackie , Ionescu-Ittu Raluca , Pivneva Irina , Wynant Willy , Shi Sherry , Wu Eric Q. , Abraham John A. 
Published: March 2020

e22527 Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive and debilitating tumor that generally affects young working-age adults. This study assessed work productivity loss in TGCT patients. Methods: Incident patients aged 18-64 years with diagnosis of TGCT, who had earning and disability data, were identified in the OptumHealth database (Q1 1999 – Q1 2017). Patients were classified into surgical and non-surgical groups depending on the presence of joint surgery claim in postindex period. Control patients without TGCT were matched 10:1 with TGCT patients on age, gender, year of TGCT diagnosis, and follow-up duration. The number of days missed from work due to disability and medical visits post diagnosis was compared using Poisson regressions. General linear models were used to compare indirect costs associated with productivity loss. Results: A total of 1,395 TGCT patients (724 surgical; 671 non-surgical) were matched to 13,950 controls (36% female; mean age = 47 years). Both surgical and non-surgical TGCT patients had more comorbidities (mean Charlson Comorbidity Index (CCI): 0.3 vs 0.2; 0.4 vs 0.2; p < 0.001), had greater use of analgesic drugs (44% vs 20%; 40% vs 21%; p < 0.001) and MRI tests (47% vs 4%; 26% vs 3%; p < 0.001) in the 12 months before TGCT diagnosis compared with controls. Both surgical and non-surgical TGCT patients missed more time from work due to disability and medical visits and had higher indirect cost associated with productivity loss than matched controls. Disability burden was greater in patients receiving surgery. Conclusions: Regardless of receiving surgery or not, TGCT is associated with significant work productivity loss. These findings highlight the unmet need for effective treatments to reduce disability and restore function in TGCT patients. [Table: see text]