bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determination of the immunogenetic risk of developing cancer.
Authors: Miklós István , Toke Eniko Rita , Megyesi Mónika , Molnar Levente , Tóth József , Lőrincz Orsolya , Somogyi Eszter , Csiszovszki Zsolt , Pántya Katalin , Páles Péter , Lori Franco , Lisziewicz Julianna 
Published: May 2019

e13132 Background: Association between certain HLA types and cancer is well known. We hypothesized that the number of epitopes of tumor antigens presented by autologous HLAs characterizes a patient’s capacity to kill tumor cells. These CD8+ T cell epitopes are presented by 6 out of >13,000 known HLA class I alleles and induce extremely variable tumor-specific T-cell responses. Methods: We predicted HLA-binding epitopes from 48 frequently expressed tumor antigens in subjects characterized with 6 HLA class I alleles. To develop the “HLA Score” cancer risk predictor we used epitopes binding to multiple HLAs of a subject. The predictor was trained on 5,789 non-American subjects. To identify populations with high and low immunogenetic risk to develop cancer we compared the HLA Score of American cancer subjects to a general population of American subjects (1,400 subjects). The performance of the predictor was characterized with AUC and Risk Ratio. Due to Bonferroni correction, AUC values with p-value p<0.007 was accepted as significant. Results: “HLA Score” predictor significantly separated cancer patients from the general population in six out of the seven investigated cancer types. The Risk Ratios between the most protected and most at risk subpopulations ranged between 2.38 and 5.67 (Table). Cancer risk prediction with HLA Score. Conclusions: Subjects with certain HLA class I alleles have high risk of developing cancer. The novel “HLA Score” predictor we introduced here could complement current testing used for determination of the genetic risk of cancer.[Table: see text]
Thank you, next: The impact of next-generation sequencing in clinical decision making.
Authors: Davis William , Makar Gabriel , Kubicek Greg J. 
Published: May 2019

e13136 Background: Next Generation Sequencing (NGS) is increasingly used to identify actionable mutations for oncology treatment. We examined the results of NGS at our institution. Methods: We retrospectively reviewed the medical charts of 305 consecutive patients who had genomic testing performed on tumor samples from March 2014 to April 2017. Next Generation Sequencing was performed by Foundation One testing. Results: Of the 305 tissue samples sent to Foundation One, 189 reports were potentially usable. Reports were unusable due to an insufficient quantity of tissue (43), inadequate follow-up (32), cessation of oncologic care due to transferring to hospice or expiring (32), or a report not being generated due to the order being cancelled (4) or undocumented reasons (5). Of the 189 usable reports, 76 (40.21%) demonstrated an aberration targetable by on-label therapies, 126 (66.67%) via off-label therapies (66 of these had no available on-label treatment), and 170 (89.94%) revealed actionable aberrations via all potential avenues, including clinical trials. 19 (6.2%) yielded a change in management, 6 of these changes were utilizing on-label therapies, 6 were via off-label therapies, 3 were via enrollment in a clinical trial, and 4 involved discontinuing a medication with a predicted poor response. For the 6 patients with off-label use, median duration of treatment was 46 days and discontinued secondary to death (3 patients) or progression (3 patients). Conclusions: Only a minority of NGS assay results (6.2% percent of all tests ordered and 10% of useable tests) resulted in a management change. A small minority (6 patients, 1.9%) were started on off-label therapy based on NSG results and overall had poor responses to off-label treatment. While in theory NGS may improve oncology outcome, the results of our initial 305 patients who had NGS was poor.
Oncobox, gene expression-based second opinion system for predicting response to treatment in advanced solid tumors.
Authors: Poddubskaya Elena , Buzdin Anton , Garazha Andrew , Sorokin Maxim , Glusker Alex , Aleshin Alexey , Allina Daria , Moiseev Alexey , Sekacheva Marina , Suntsova Maria , Kim Ella L , Gaifullin Nurshat , Tkachev Victor , Giese Alf , Barbara Viktoria , Borger Pieter , Borisov Nikolay 
Published: May 2019

e13143 Background: Anticancer Targeted Drugs (ATDs) specifically target one or a few types of tumor-related molecules in a cell. More than two hundred of ATDs were approved worldwide. They have different mechanisms of action and are effective for different cohorts of patients. However, many individual cases remain poorly responsive and it is of great importance to identify predictive markers of ATD efficacy. Our aim was to develop a platform enabling smart selection of the most efficient ATD therapies. Methods: We generated a second-opinion platform for clinical oncologists termed Oncobox. It is based on the analysis of gene expression profile of a cancer sample in comparison with the corresponding normal tissue biosamples in order to personalize selection of targeted drugs for individual cancer patients. Based on RNA-seq gene expression data, pathway activation levels are calculated and along with the concentrations of molecular target genes products used as predictors of tumor response to ATDs. Results: The Oncobox method was tested first on the retrospective samples of advanced tumors: gastric, renal cell, ovarian and colorectal cancers, thus showing ROC AUC values > 0.7. In currently ongoing prospective trial for advanced solid tumor patients, the Oncobox tests were completed for 239 patients, primary feedback information received for 144 patients. 25 patients (17%) died before prescription of the therapy, 19% received palliative care treatment, 39% received Oncobox-recommended therapies and 25% received other therapies (February 2019). Tumor responses were estimated for 30 patients (breast, colorectal, ovarian and other cancers) receiving therapies, with disease control rate of 71% for Oncobox-recommended ATDs (Bevacizumab, Crizotinib, Trastuzumab and others) and 44% for other therapies. Our results also suggest that cancer metastases and primary tumors may have different gene expression, molecular pathway activation and drug scoring patterns, thus pointing to the importance of testing multiple tumor sites. Conclusions: Our study suggests that profound analysis of gene expression profiles of tumor tissues may be useful for ATDs treatment of advanced and metastatic cancers. Clinical trial information: NCT03724097.
Specific clonal expansion at disease progression (PD) in solid cancers pinpointed by cell free DNA analysis.
Authors: Frullanti Elisa , Palmieri Maria , Baldassarri Margherita , Fava Francesca , Fabbiani Alessandra , Gelli Elisa , Tita Rossella , Torre Pamela , Petrioli Roberto , Hadijstilianou Theodora , Galimberti Daniela , Cinotti Elisa , Mencarelli Maria Antonietta , Pinto Anna Maria , Francini Edoardo , Marsili Stafania , Francini Guido , Renieri Alessandra 
Published: May 2019

e13144 Background: More than 50% of solid cancers sooner or later escape control of standard treatments. Detection and analysis of cell free circulating DNA (cfDNA) now offer the possibility to detect key mutations of cancer driver genes which may play a major role in the therapy escaping mechanism. We sought to identify clones of solid tumors escaping standard treatments in order to assess personalized treatment at PD. Methods: A cohort of patients with 10 different solid tumors progressing after standard therapy were selected. CfDNA analysis was performed using PAXgene blood ccfDNA tubes (QIAGEN), MagMAX cell-free total nucleic acid isolation kit, and ION PROTON platform (ThermoFisher Scientific). Results: Next generation sequencing analysis of 52 cancer-driver genes of cfDNA samples of 39 patients allowed for picking up clones plausibly involved in the PD mechanism in 60% of cases. A mean of 1.3 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and CNV in FGFR3 were the most commonly observed, with a rate of 41%, 16%, and 13%, respectively. Increased copy number variations of FGF receptors were identified in patients with non-small cell lung, pancreatic, and gastric cancer, and cholangiocarcinoma. Other clones had mutations in ESR1 (breast), CTNNB1 (uterus), KRAS and CCND2 (pancreas), EGFR and BRAF (lung). Interestingly, retinoblastomas resistant to Melphalan showed expanding mutated clones in PTEN or SMAD4. Increased levels of cfDNA were observed in the plasma of all patients. Conclusions: The results presented here show that irrespective of the primary tumor mutational burden and subsequent complex clonal evolution, a simplified mutational load is present at PD. One or few “sniper” clones drive progression and the molecular profile has a weak correlation with the primary tumor. Single driver mutations in TP53 remain the main target of a not yet developed specific therapy in most tumors such as breast, ovarian, uterine, lung, gastric cancers and glioblastoma. Among the actionable mutations, PIK3CA were found, not only in breast cancers, but also in uterine carcinoma, Sezary syndrome and glioblastoma, pinpointing the needs of specific trials in these tumors.
Germline analysis of DNA-damage repair genes in men with advanced prostate cancer in comparison to women with breast cancer.
Authors: Kunz Amy , Tri Natalie , Samiei Arash , Mao Shifeng 
Published: May 2019

e13147 Background: Women with breast cancer have traditionally been the population for genetic counseling. The association of hereditary cancer syndromes and the development of advanced prostate cancer have been established only since recent years. There has been increased utilization of germline analysis in men with prostate cancer since NCCN updated its guideline on genetic testing for DNA damage repair (DDR) genes in the homologous recombination (HR) pathway in this population. In this study, we analyzed the prevalence of genetic alterations in DDR genes in men with advanced prostate cancer in relevance to women with breast cancer in our institution. Methods: Patients who were referred to genetic counseling in 2018 and met NCCN criteria underwent genetic testing following pretest genetic counseling. Samples obtained from buccal mucosa or peripheral blood were analyzed for germline variants using commercially available multi-gene panels which included DDR genes in the HR pathway. Results: In 2018, 54 men with prostate cancer with relapsed disease following local therapy, or de novo metastasis, and 305 women with breast cancer were included. At least one pathogenic or likely pathogenic variant was identified in 9 men (16.7%), most frequently in BRCA2, ATM, and CHEK2, as compared to those in 30 women (9.8%), p = 0.137. 17 men (31.5%) had at least one variant of uncertain clinical significance (VUS) detected in a DDR gene as compared to those in 74 (24.3%) women with breast cancer, p = 0.261. Conclusions: Men with advanced prostate cancer have a statistically comparable but numerically trending higher frequency of pathogenic variants and VUS in DDR genes detected on germline testing in comparison to women with breast cancer. The high prevalence of VUS in prostate cancer is an intriguing finding. VUS represent a genetic alteration with undefined clinical outcome. With increasing genetic testing in prostate cancer, further correlation between VUS of DDR genes and clinical risk features from a larger population is warranted.
Auxiliary diagnosis of pulmonary nodules using liquid biopsy and deep learning/techniques.
Authors: Bai Li , Zhou Yanqing , Chen Yaru , Liu Quanxing , Zhou Dong , Zheng Hong , Dai Jigang 
Published: May 2019

e13154 Background: Many people harbor pulmonary nodules. Such nodules can be detected by low-dose computed tomography (LDCT) during regular physical examinations. If a pulmonary nodule is small (i.e. < 10mm), it is very difficult to diagnose whether it is benign or malignant using CT images alone. To address this problem, we developed a method based on liquid biopsy and deep learning to improve diagnostic accuracy of pulmonary nodules. Methods: Thirty-eight patientsharboring one or more small pulmonary nodules were enrolled in this study. Twenty-nine patients were diagnosed as having cancer (stage I = 21, stage II = 1, stage III = 3, stage IV = 4) using tissue biopsy, while the other 9 patients were diagnosed as having benign tumors or lung diseases other than cancer. For each patient, a blood sample was obtained prior to biopsy, and the cell free DNA (cfDNA) was sequenced using a 451-gene panel to a depth of 20,000×. The unique molecular identifiers (UMI) technique was applied to reduce false positives. Seventeen patients also had full-resolution CT images available. A deep learning system primarily based on deep convolutional neural networks (CNN) was used to analyze these CT images. Results: Sequence analysis of blood samples revealed that 75.8% (22/29) of cancer patients had detectable cancer related mutations, and only 1 of 9 (11.1%) non-cancer patient was found to carry a TP53 mutation. The most frequent mutations seen in cancer patients involved genes TP53 (N = 11), EGFR (N = 7), and KRAS (N = 3) with mutant allele fractions varying from 0.08% to 74.77%. Deep learning analysis of the 17 available CT images correctly identified cancers in 88.2% (15/17) of patients. However, by combining the liquid biopsy and image analysis results, all 17 patients were correctly diagnosed. Conclusions: Deep learning-based analysis of CT images can be applied to early diagnosis of lung cancers; but the accuracy of image analysis, when used alone, is only moderate. Diagnostic accuracy can be greatly improved using liquid biopsy as an auxiliary method in patients with pulmonary nodules.
EMR documentation of genetics evaluations in patients with ovarian cancer.
Authors: Shah Payal Deepak , Symecko Heather , Batson Melissa , Pundock Stacy , Rustgi Neil , Haggerty Ashley Ford , Ko Emily Meichun , Martin Lainie P. , Nathanson Katherine , Domchek Susan M. 
Published: May 2019

e13156 Background: Genetic testing for hereditary cancer predisposition has become increasingly complex yet impactful. Provider knowledge of test results influences risk management, implications for family members, and therapeutics. Currently, it’s unknown if genetic test (GT) results are appropriately recorded and accessible within the electronic medical record (EMR). Methods: We conducted a single-institution retrospective chart review to examine clinical diagnoses, family history of cancer, genetics referrals, and genetics services received at University of Pennsylvania’s Cancer Risk Evaluation Program (CREP) or elsewhere. The study cohort included new and prevalent cases of ovarian cancer (OC) seen by either a gynecologic or medical oncologist at the University of Pennsylvania in 2016. Analyses were conducted using SAS 9.4. Results: 667 women (83% white, 9% black, 4% Asian; mean age 61) with OC were included. 58% had a documented family history of breast, ovarian, prostate or pancreas cancer. 48% had documentation of referral to genetic testing and an additional 26% had documentation of testing outside of CREP. 26% had no documentation of referral or testing. Of those referred to CREP, 75% had genetic testing: in total 62% of the cohort had documented testing. 94% of those tested had a result documented in a provider note, and 64% had a scanned testing report uploaded into the EMR, including 74.3% of those tested through CREP and 25.7% of those tested outside. Among the 118 pathogenic mutations, 70% were documented on the EMR “problem list.” Conclusions: In this study, most, though not all, OC patients had documentation of a GT referral or testing in the EMR. Although GT results were routinely included in progress notes, these reports were less commonly scanned into the EMR (particularly for those tested outside Penn) or included in the EMR “problem list” which is both searchable and immediately visible. Capturing genetic data in a uniform and easily accessible manner within the EMR is necessary to maximize clinical utility of this information and should be a focus for EMR module development.
Effect of SSH1/SSH2 expression changes by shRNA in glioma cell lines on response to radiotherapy and cofilin-1 reactivation.
Authors: Xiao Hong 
Published: May 2019

e13505 Background: Radiotherapy has become the most important treatment for malignant glioma following surgery. However, development of radioresistance in glioma cells limits therapeutic efficacy. The slingshot (SSH) family of phosphatases is a potent regulator of Cofilin-1 activation. Methods: We investigate the role of SSH1(slingshot protein phosphatase 1) and SSH2 in radioresistance via using shRNA to block SSH1/2 expression in U251 and U373 cells as well as established radioresistant U251 (RR-U251) and U373 (RR-U373) cells. Results: We found that both SSH1 and SSH2-shRNA efficiently sensitized glioma cells to radiation with a sensitization enhancement ratio (SER) of 1.01-1.73. In SSH1-silenced cells, the cell viability, migration, and invasion abilities following radiation were remarkably reduced and radiation induced cell apoptosis was markedly enhanced compared with control cells. While in SSH2-silenced cells, the alterations were not as significant. Furthermore, the result of Western-blot suggested that radiosensization of SSH1/SSH2 silencing was mediated by inhibiting reactivation of phosphorylated CFL-1. Conclusions: Our study demonstrated that SSH1 and SSH2 are valid radiosensitizing targets in not only normal glioma cells but radioresistant lines, suggesting a novel therapeutic strategy to improve the efficacy of radiotherapy in patients with glioma.
The effect of everolimus on CNS penetration and efficacy of dasatinib in the treatment of PDGFRA-driven glioma.
Authors: Miklja Zachary , Mullan Brendan , Siada Ruby , Stallard Stefanie , Yadav Viveka Nand , Bruzek Amy , Garcia Taylor , Leonard Marcia , Robertson Patricia , Paul Alyssa , Pai Manjunath , Phoenix Timothy , Marini Bernard , Koschmann Carl Johannes 
Published: May 2019

e13508 Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase CNS penetration and efficacy of dasatinib in in vitro and in vivo models as well as in human PDGFRA-driven glioma. Methods: Tumors were generated in mice using an intra-uterine electroporation (IUE) model [introduction of TP53, PDGFRA and H3K27M mutations in pre-natal cortex]. Dose response, synergism studies, P-GP inhibition and pharmacodynamics/pharmacokinetic studies were then performed on in vitro and in vivo models employing this IUE system. A phase 2 trial employing dasatinib and everolimus was established for children with HGG and diffuse intrinsic pontine glioma (DIPG) that contain PDGFRA alterations (NCT03352427). Paired CSF/plasma samples (before and after addition of everolimus) were collected from enrolled patients. Results: Dasatinib effectively treated mouse HGG cells with an IC50 of 100 nM. Dose-dependent reduction in PDGFRA and pPDGFRA was found. P-gp inhibitor assay confirmed that everolimus strongly blocks P-gp activity at 1 uM (p = 0.0028 vs untreated). Mice treated with dasatinib and everolimus had extended survival as compared to control. Two-hour exposure to everolimus resulted in sub-IC50 dasatinib concentration in cortex (23 nM) and tumor (65 nM). 24-hour exposure to everolimus resulted in greater cortex (235 nM) and tumor (509 nM) concentrations. Two trial patients, recurrent HGG ( PDGFRA-amplified) and recurrent DIPG ( PDGFRA D842V) respectively, survived 6 months and 9 months (ongoing) after progression, which compares very favorably to historical controls. A paired CSF sample from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. Conclusions: Dasatinib treatment of PDGFRA-driven HGG is improved with everolimus blockade of P-gp and represents a novel route for improving CNS penetration and efficacy of therapies for HGG. Clinical trial information: NCT03352427.
Circulating endothelial cells: Prognostic value in patients with glioblastoma.
Authors: Vaz Salgado María Ángeles , Earl Julie , Berrocal Victor Rodriguez , Salge Freddy , Gomez Ana , Corral de la Fuente Elena , Sepulveda Sanchez Juan Manuel Manuel , Perez-Núñez Angel , Muriel Alfonso , Lourido Daniel , Carrato Alfredo , Ley Luis 
Published: May 2019

e13517 Background: Glioblastoma (GB) is an aggressive tumor. Circulating Endothelial Cells (CECs) can be detected in peripheral blood and have been related to angiogenesis. CECs have an unclear prognostic value in patients with glioblastoma. The objective of this study was to quantify the presence and number of CECs in GB patients and determine its potential prognostic role. Methods: In this prospective, single center study, peripheral blood samples were obtained at the time of GB diagnosis. For the detection of CECs, 4 ml of blood was analyzed using the CellSearch system (Veridex). CEC blood samples were classified as CD146+, CD105+, CD45− and DAPI+. CEC detection was performed prior to surgery in a total of 26 patients and 22 patients with glioblastoma were included in the final analysis. We mesured progression free survival (PFS) and overall survival (OS). Results: Between 2014 and 2016, twenty two patients with histologically confirmed glioblastoma were studied. There were 14 males and 8 females with an average age of 63 years (range 42-81). A complete resection was achieved in 50% of cases, partial or subtotal resection in 31.8% and biopsy in 18%. The mean number of CECs was 59.3 cells/mL (range 0-954). Patients were classified into two groups depending on the number of CECs: group 1 had a CEC count below the mean and group 2 had a CEC count above the mean. A total of 17 patients (77.2%) were in group 1 and 5 patients (22.7%) were in group 2.The median OS was 14.4 months (range -0.36-33.36) for the entire study population. The median OS was 17.4 months (IC95% 11.47-23.37) for patients in group 1 and 8.12 months for patients in group 2 (IC 95% 4.38-11.85) p = 0.002. The median PFS was 8.94 m (IC95% 5.1-12.69) for group 1 and 3.95 for group 2 (IC 95% 2.91-4.98) p = 0.097. Conclusions: CECs can be detected in recently diagnosed GB patients. The present study demonstrates a possible prognostic value for CEC determination in GB cases at the time of diagnosis.