bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune-related adverse events for different age groups using the FDA Adverse Event Reporting System.
Authors: Myint Zin , Qasrawi Ayman , O'Neal Richard , Thomas Chris Z , Arnold Susanne M. , Wang Peng 
Published: May 2019

e14256 Background: Understanding immune-related adverse events (irAEs) for different age groups is crucial in the era of immunotherapy. The aim of our study is to assess the irAE profiles in different age groups (≤65 and > 65 years) for drugs that target PD1/PDL1, CTLA4, and their combination. Methods: Data were obtained from the FDA Adverse Event Reporting System database from Jan 2014 to Sep 2018. We extracted the data based on reported irAEs and reviewed 30 different irAEs including, but not limited to colitis, pneumonitis, interstitial lung disease (ILD), myocarditis and pneumonitis. Cases with missing data, another drug reported with the PD1/PDL1 or CTLA4 combinations, and duplicate cases were excluded. We calculated the reporting odds ratio (ROR) for irAE associated with the use of PD1/PDL1, CTLA4 and combination, respectively. Results: A total of 6197 reported irAEs cases were included: 3140 cases from patients ≤65 years and 3057 from > 65 years old. Colitis was the most common irAEs in both groups. The RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.17 (3.47-5.02), 0.6 (0.5-0.72), 1.98 (1.64-2.39) for colitis; 0.21 (0.09-0.52), 2.94 (1.97-4.38), 2.2 (1.46-3.3) for diabetic ketoacidosis; 0.29 (0.09-0.92), 16.5 (6.54-41.9), 0.18 (0.04-0.73) for rheumatoid arthritis in ≤65 age group. In > 65 age group, the RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.79 (3.49-6.58), 0.56 (0.4-0.78), 2.84 (2.06-4) for hypophysitis; 0.12 (0.06-0.24), 28.53 (18.5-44), 0.17 (0.1-0.29) for interstitial lung disease (ILD); 0.38 (0.19-0.78), 2.87 (2.01-4.1), 2.41 (1.64-3.54) for myocarditis. When we compared all the studied irAEs between age groups (≤65 and > 65) by ROR, the only statistically significant irAE was ILD. The RORs (95%CI) for ILD associated with PD1/PDL1 in age≤65 and > 65 were 11.3 (7.65-16.8) & 28.53 (18.49-44.02). Conclusions: There was no significant difference between irAEs in different age groups except with ILD, which is more commonly seen in the > 65 age group. The ROR combination irAE profiles provide hypothesis generating information regarding association between irAEs and the use of various immune therapies.
Surface programmable activation receptor (SPAR) cell platform for the rapid detection of melanoma-specific biomarkers.
Authors: Lwande Joel , Kittle Joseph D , Williams M. Russell , Liang Shengwen , McQuaid Kyle , Frenchmeyer Melissa , Tang Yuanyuan , Neese Allison , Hua Jiangzhou , McBrairty Charles 
Published: May 2019

e14263 Background: We have previously demonstrated that SPAR modified T cells effectively detect bacterial and viral pathogens. SPAR cells are engineered to express a modified T cell receptor (TCR) capable of antibody-directed signal transduction and respond with a Ca2+-mediated production of luminescent signal upon target detection. Here we describe the ability of SPAR cells to rapidly detect the cell surface expression of melanoma biomarkers without a requirement for extensive sample preparation. Methods: SPAR cells expressing both an engineered T cell receptor and the luminescent reporter protein aequorin were developed via the transfection of Jurkat cells with the aequorin expression vector pEF1-Aeq and an engineered TCR complex composed of mouse FcγRI fused to the CD3ζ subunit. The mFcγRI-CD3ζ receptor binds to the Fc region of full-length mouse IgG2 antibodies: SPAR cells are programmed for target detection via the addition of target-specific antibody. The ability of programmed SPAR cells to accurately detect melanoma-specific cell surface biomarkers was evaluated using whole cells from cultured mouse (B16-F10) and human (SK-Mel-28) melanoma cell lines. SPAR cells were programmed by incubation with murine antibodies directed toward the melanoma biomarkers CD133 or TRP1, then mixed with melanoma cells or K562 control cells and evaluated for signal generation. Results: SPAR cells programmed with anti-CD133 or anti-TRP1 antibody produced luminescent signal within minutes when combined with human SK-Mel-28 cells or mouse B16-F10 cells, respectively, known to abundantly express the appropriate biomarker. No signal was generated when programmed SPAR cells were incubated with K562 cells. Further studies also document cytokine production following receptor engagement. Conclusions: SPAR cells can be programmed for the rapid and specific detection of known cell surface cancer biomarkers. The Ca2+-dependent production of luminescent signal and cytokine release in response to TCR engagement suggests SPAR cell activation. Thus, in addition to biomarker detection the SPAR system may ultimately provide predictive insights into the potency of antibody-directed cell therapy.
NSCLC mutation frequency in the central American and Caribbean region.
Authors: Corrales-Rodriguez Luis , Arauz Erik Alexander , Bacon Fonseca Ludwing Alexander , Lanza Mario , Matos Luis Homero , Vargas Carmen 
Published: May 2019

e14278 Background: Lung Cancer (LC) constitutes a leading cause of death in the World. Non-small cell lung cancer subtype adenocarcinoma (NSCLC-A) has been associated with epidermal growth factor receptor (EGFR) mutations, which is essential for treatment decisions. The EGFR mutation frequency has been proven to have regional variability in this NSCLC-A population. The current study presents the EGFR mutation incidence and T790M frequency in NSCLC-A cases diagnosed in Central American and Caribbean(CA&C) region. Methods: A cross-sectional evaluation was performed in patients diagnosed with NSCLC-A between 2016 and 2018 in five CA&C countries. Patients were obtained from Reference Centers in Dominican Republic, Nicaragua, Panama, Honduras and Costa Rica through the AstraZeneca testing program. EGFR mutations were evaluated through Real-Time PCR. Results: The research included 972 cases. Mean of age at the diagnosis was 62.79(28.12-90.46) years. Overall distribution of cases by gender was female in 52.37% (509/972) and male in 47.64% (463/972). For the group of antiEGFR TKI naïve patients, tissue samples were processed in 67.83% (601/886). For the group of post antiEGFR TKI patients plasma samples were processed in 90.70% (78/86). For the group of antiEGFR TKI naïve patients, EGFR mutations were present in 26.64% (236 / 886), the mean of age was 63.17 years (28.12-113.47). The frequency of Exon 19 was 53.38(126/236)% and Exon 21 was 27.54%(65/236)% and 11.01% (26/236) were complex mutations. T790M mutations in this treatment naïve population was 2.14%(19/886). For the group of post antiEGFR TKI patients the frequency of T790M mutation was 50.00% (43/86) where 78.57% were obtain from plasma samples. Conclusions: The frequency of NSCLC EGFR mutation positive patients in the CA&C region was similar to that previously described in other Latin American (LA) countries. In the treatment naïve population, tissue samples remain the most important sample to analyze for EGFR mutations. T790M mutations can be seen in treatment naïve population. For patients that progressed to an antiEGFR TKI, T790M mutations were seen in a similar frequency as describe in previous LA countries. For post antiEGFR TKI patients, plasma samples were the preferred method to evaluate T790M mutations with an adequate sensibility.
Development of a PD-L1 multiplex immunofluorescence assay with advanced visual analysis for understanding the tumor microenvironment.
Authors: Downing Sean , Sharma Aditi , Hebert Courtney , Buell Jamie , Wood Douglas 
Published: May 2019

e14283 Background: Current PD-L1 Immunohistochemistry (IHC) assays utilizing conventional brightfield, chromogenic 3,3′-Diaminobenzidine (DAB) staining modalities are the norm in both translational and clinical research. With the rise of immuno-oncology, multiplexed immunofluorescence (mIF) has the potential to revolutionize pathology research as it enables the identification of complex cell phenotypes and their potential interactions in the tumor microenvironment (TME). Ultivue has developed a mIF assay for profiling PD-L1, CD8, CD68, pan-Cytokeratin, and Sox10 enabling whole-slide imaging and data analysis in a single workday. Methods: With an expanding number of biomarkers being interrogated, the complexity of the data analysis and visualization tasks increase exponentially. For N markers, a total of 2N phenotypes are possible. To address this problem and reveal the biologically relevant information embedded in the data, we have developed software tools to reduce the complexity, visualize, and quantify spatial distributions of cells across the full spectrum of possible phenotypes. In this study we demonstrate the utility, robustness, and ability to derive meaningful biological insights by validating the accuracy, precision, sensitivity, and specificity of the PD-L1 multiplex immunofluorescence assay. Results: Here we present results that identify all distinct binary phenotypes within cohorts of lung cancer and melanoma samples using qualitative pathology review and an image processing technique called Phenotypic Surface Density Mapping (PSDM). Important features of this quantitative technique are robustness, use of real physical units (e.g. cells/µm2 or intensity/µm2), and data generation in an unbiased fashion to reveal information about every possible phenotype. Conclusions: Applying the pathology review and PSDM to the cohorts of samples confirmed a high level of concordance demonstrating sensitivity and specificity with high degrees of confidence above 85%. Analysis of intra-run, inter-run, and inter-technician runs revealed that cell counts were within a CV less than 15% across all markers. Data presented here indicates the potential for use in a high throughput testing laboratory to aid in collection and interpretation of meaningful biological insights.
Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels.
Authors: Matikas Alexios , Zerdes Ioannis , Lovrot John , Richard François , Sotiriou Christos , Bergh Jonas C. S. , Valachis Antonios , Foukakis Theodoros 
Published: May 2019

e14284 Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE). Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed. Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p < 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p < 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p < 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p < 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p < 0.001 for OS), pinteraction 0.124 for DFS and 0.005 for OS. Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.
Changes in tumor mutational burden in serially biopsied non-small cell lung cancer.
Authors: Smithy James W. , Hwang David H. , Li Yvonne Y. , Spurr Liam , Cherniack Andrew D. , Sholl Lynette M. , Awad Mark M. 
Published: May 2019

e14286 Background: High tumor mutational burden (TMB) has been associated with response to checkpoint blockade in non-small cell lung cancer (NSCLC) and other malignancies. However, the degree to which TMB changes over time, across anatomical sites, and with intervening treatment remains unknown. To evaluate TMB changes across time points, we compared TMB in tissue specimens from patients with serially-biopsied NSCLC. Methods: Clinicopathologic characteristicsand changes in TMB were analyzed from patients with NSCLC and more than one biopsy that had undergone targeted next generation sequencing (NGS, OncoPanel) at the Dana-Farber Cancer Institute. Those representing distinct primary tumors by histology and/or discordant mutational profiles were excluded. Results: 134 NSCLC patients with more than one interpretable NGS result were identified; 23 were excluded due to separate primary tumors. Of the 111 remaining patients included in the analysis, the median time between samples was 14 months (range: 0 to 114 months). TMB correlated closely across all matched tumor pairs (Pearson’s r = 0.89), and greater variability in TMB was seen in biopsies taken from different anatomic sites (p = 0.04) compared to biopsies obtained from the same lesion. There was no significant change in median TMB with any intervening therapy, as TMB increased in some patients and decreased in others. Conclusions: In this observational study, TMB correlated closely across tumor pairs. However, these data suggest that sampling from different tumor sites may be associated with greater discrepancies in TMB. It is possible these differences could account for challenges in using TMB as a predictive biomarker for immunotherapy response. Further prospective investigation is needed to inform decisions regarding the need for repeat biopsy in patients starting immunotherapy with remote tissue samples.
BRCA 1/2 mutations in high-grade serous ovarian cancer (HGS-OC) patients of three Latin American countries: Report of 412 cases.
Authors: Molina Juan , Castillo Fernandez Omar Orlando , Lim Maria , Mas Luis , Veliz Ignacio Fernando , Vargas Carmen 
Published: May 2019

e14288 Background: Ovarian Cancer (OC) is the most common gynecologic cancer in women in the World and with elevated mortality. High Grade Serous Ovarian Cancer (HGS-OC) is a common histotype and closely related with the presence of BCRA abnormalities. This is to our knowledge the first report of a large series of patients with HGS-OC evaluated in Latin-American countries. The study aim was to present the data obtained from Perú, Costa Rica and Panamá from January 2016 to December 2018. Methods: A cross-sectional evaluation was performed in patients diagnosed between 2016 and 2018 with HGS-OC in three countries in Latin America. The patients were selected from Cancer National Reference Centers in Perú, Panamá and Costa Rica. Germline BRCA 1 / 2 mutations were evaluated through Next Generation Sequencing (NGS) in blood samples. Results: During the period 412 HGS-OC were studied. The mean age at diagnosis was 56.55(SD:12.21) years for all the evaluated patients and 55.42(SD:8.60) years in the mutated cases. Pathogenic HGS-OC mutations in germline BRCA 1 / 2 were diagnosed in 72 cases. Germline BRCA 2 mutations were the most frequent abnormality detected in Panama and in Costa Rica with 70.0 %(7/10) and 77.8%(14/18), respectively. However in Perú, germline mutations in BRCA 1 represents the majority of the mutations with 79.3%(35/44). Variants of uncertain significance (VUS) were detected in 3.64 %(15/412). Positive family history for breast or ovarian cancer were detected in 13.8% of patients with pathogenic mutations(10/72). Specific mutation distribution evidenced in Perú that 6 of 44(13.6%) mutated patients had the mutation in BRCA 1 c.2105dupT; 6 patients of 18(33.3%) had the mutation in BRCA 2 c.5303_5304delTT in Costa Rica and 2 cases had the mutation in BRCA1 c.5186C > A in Panama. The rest of mutations were less common. Conclusions: The frequency of Germline mutations BRCA 1 and BRCA 2 in patients with HSG-OC is similar to the reported in developed nations. However, the different mutation profile between the studied countries could be explained by the Latin-American genetic diversity. Most of the mutations we report were not described in previous studies evaluating breast cancer susceptibility.
Immune checkpoint inhibitor response in tumors with LRP1B variants.
Authors: Zhu Jason , Tucker Matthew D , Kao Chester , Labriola Matthew , Cheris Sachica , Datto Michael B. , Wu Yuan , Healy Patrick , Gupta Santosh , Kirtane Kedar , Gupta Rajan T. , Marin Daniele , Zhang Tian , McNamara Megan Ann , Harrison Michael Roger , George Daniel J. , Armstrong Andrew J. 
Published: May 2019

e14291 Background: Low-density lipoprotein receptor-related protein 1B (LRP1B) is a putative tumor suppressor gene spanning > 500 kb on chromosome 2. A melanoma study previously reported enrichment of LRP1B mutations in responders (34%) to immune checkpoint inhibitors (ICIs) compared with non-responders (3%). Deep deletions in LRP1B are frequently observed in non-small cell lung cancer (NSCLC, 12%), head and neck (11%), cervical (9%), bladder (8%), and prostate cancers (8%). This study examines the clinical response to ICIs in a diverse group of tumor types with LRP1B alterations. Methods: We conducted a single center retrospective study inclusive of all patients (pts) with tumors containing any LRP1B variant who were treated with an ICI between 01/2015 and 11/2018. The primary outcome of the study was to describe the clinical outcomes of patients with LRP1B alterations, with respect to radiographic response to therapy, time on therapy, duration of response, and overall survival. Results: 44 pts with an LRP1B variant were treated with an ICI at Duke between 01/2015 and 11/2018. The most common ICIs were pembrolizumab (29/44, 66%) and nivolumab (12/44, 27%). Tumor types included NSCLC (24/44, 55%), renal cell carcinoma (RCC, 5/44, 11%), and prostate cancer (5/44, 11%). 14 (32%) pts had pathogenic variants (PVs) and 30 pts (68%) had variants of uncertain significance (VUS). Among pts with LRP1b PVs, 36% (95%CI 14%-64%) had radiographic responses (5/14, 2 lung, 1 prostate, 1 RCC, 1 endometrial carcinoma), two of whom were MSI high. As a control, the radiographic response rate among patients with a LRP1b VUS was 10% (95%CI 3%-28%). Of those with PVs, 3 pts had stable disease, one of whom has been on CPI therapy for > 22 months and 5 (36%) remain on therapy, with 2 (14%) pts discontinued due to immune toxicities, and 7 (50%) pts discontinued due to disease progression. The median TMB among responders was 12 (2-150.05 mut/Mb) and the median TMB amongst non-responders was 9.5 (6-18 mut/Mb). Conclusions: In a tumor agnostic population of pts harboring LRP1B PVs, 36% of pts have responses to ICI. The majority of responders were MSS and TMB low, which may suggest that PV in LRP1B may independently predict for response to ICI. Prospective and multicenter validation is now needed.
Human model to predict the outcome of cancer vaccine clinical trials.
Authors: Lőrincz Orsolya , Toke Eniko Rita , Somogyi Eszter , Csiszovszki Zsolt , Megyesi Mónika , Pantya Kata , Tóth József , Molnar Levente , Miklós István , Lori Franco , Lisziewicz Julianna 
Published: May 2019

e14298 Background: Cancer vaccines activate T-cells with peptides presented by HLA alleles. We hypothesized that peptides binding to multiple HLA alleles of a patient are more likely to induce T-cell responses than epitopes presented by a single HLA. To prove this hypothesis we predicted the outcome of vaccine clinical trials in a Model Population of subjects with complete HLA genotype. Methods: We collected the immune- and objective response rate (IRR, ORR) results from 64 clinical trials conducted in 1,790 patients treated with 42 different vaccines. From these 42 vaccines, we identified personal epitopes (PEPIs) with strong binding affinity to at least 3 HLA alleles of each subject in the Model Population and calculated the proportion of subjects with PEPIs (PEPI Score), multiple PEPIs (MultiPEPI-Score) and PEPIs against multiple vaccine antigens (MultiAg PEPI-Score). Results: Highly significant correlation between the PEPI Score and IRR (p = 0.001) suggests that peptides binding to at least 3 HLA alleles of the subject induce T-cell responses. MultiPEPI-Score correlated with ORR when the tumor of patients expressed the target antigen (p = 0.01). MultiAg PEPI-Score correlated with ORR of clinical trials conducted with vaccines containing multiple antigens (p = 0.01). Conclusions: Our results suggest that (i) a patient’s HLA genotype is the main determinant of vaccine response and (ii) T-cell responses against multiple antigens expressed in the patient’s tumor favors tumor shrinkage. We introduced a novel pre-clinical human model that accurately predicts the outcome of clinical trials, will reduce the risk, cost and time of vaccine development for the prevention and treatment of cancer.
Low-coverage whole genome sequencing of FFPE-derived-DNA and extracellular vesicle-associated DNA in patients with metastatic cancer.
Authors: Nguyen Bella Hai , Wong Nick , Semple Timothy , Ruhen Olivia , Wong Stephen Q , Leslie Connull , Mirzai Bob , Millward Michael , Meehan Katie , Lim Annette May Ling 
Published: May 2019

e14523 Background: Low-coverage whole genome sequencing (LC-WGS) of tumors provides valuable insight into molecular changes driving oncogenesis. A novel liquid biopsy source of tumor DNA for analysis is from extracellular vesicles (EV) obtained from blood. This study compared copy number alteration (CNA) profiles generated from LC-WGS of Formalin-Fixed Paraffin-Embedded (FFPE) DNA and EV-associated DNA in cancer patients. Methods: Three metastatic base of tongue (BOT), two of which were Human Papillomavirus-related (HPV+) and two metastatic cutaneous squamous cell carcinoma (cSCC) patients were included. EV were isolated using ultracentrifugation from patients’ plasma. DNA was extracted from FFPE tumor tissue and EV. LC-WGS aiming for 0.5-1X coverage was performed using a validated method. CNA profiles were generated using the QDNAseq package, with gains defined as a log2 ratio ≥0.15 and losses < -0.15. Results: CNA profiles of FFPE samples from BOT patients demonstrated significant variation regardless of HPV status, with a mean of 20 regions containing 125 CNA (amplifications or deletions) per sample. The cSCC FFPE samples demonstrated a mean of 23 regions containing 189 CNA per sample. Overall, EV-associated DNA CNA profiles had limited similarity with primary FFPE. EV-associated DNA showed a lower number of CNA regions and CNA, with a mean of 3.7 CNA regions and 11.4 CNA for BOT samples and 6.5 regions and 15.9 CNA for cSCC samples. The HPV-BOT sample showed 2/3 EV-CNA regions matched corresponding FFPE-CNA profile (n = 15). The two HPV+ samples were less consistent with only 1/3 and 1/5 EV-CNA regions matching FFPE-CNA profiles (n = 39 and n = 6, respectively). The two cSCC cases showed more consistency with 4/6 and 6/7 EV-CNA regions matching FFPE-CNA profiles (n = 21 and n = 25, respectively). In the matched CNA regions, the mean CNA in EV-associated DNA was 7.5 and in FFPE-DNA was 97. Conclusions: Although selected EV-associated DNA CNA regions reflected the primary tumors, these were limited in number and did not globally reflect the FFPE derived CNA profiles.