bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory biomarkers as pronostic factors of mortality in critical ILL oncology patients at ICU.
Authors: Aliaga Macha Carlos , Runciman Thanya , Carracedo Carlos F. 
Published: May 2019

e14535 Background: Inflammatory markers have been used as prognostic factors in multiple malignancies.In cancer patients, critically ill, the utility of these have limited data.The aim of our study is to determine whether neutrophil lymphocyte ratio (NLR) or lymphocyte platelet ratio(PLR) are prognostic factors for mortality in critically ill patients. Methods: We retrospectively analyzed data of 79 patients with solid tumors admitted to ICU at Sanna-Aliada Clinic between January 2018 to December 2018. Inflammatory markers results were obtained from laboratory tests performed during the first 24h of admission to ICU. Receiving operating characteristic (ROC) curves were constructed and the sensitivity, specificity, predictive values and probability indicators for the NLR and PLR. Results: A total of 79 patients were assessed, 39 women and 40 men. The average age was 60.28 years, median of 61 ( 18 to 91). 51.9% had metastatic disease. The most frequent places were lung 12 (15.2 %) and brain 9 (11,4%) . The main cause for admission to ICU was infectious disease (40.5%). The analysis of normality (Kolmogorov-Smirnov test) indicates that the variables age, hemoglobin, leukocytes, platelets, neutrophils, lymphocytes, have a normal deviation while the other variables: lactate, PCR, neutrophil to lymphocyte ratio (NLR) , Platelet to lymphocyte ratio (PLR) are not distributed normally. Regarding mortality, 44 patients were alive at 30 days (66.7%), and 30 (45.5%) were alive at 90 days. The average stay in the ICU was 8.43 days, with a median of 6, (SD 7.17, 1 to 40 days), 22.8% died in the ICU. The evaluation of PLR and NLR as a mortality marker is significant for the group of patients admitted to the ICU due to a noninfectious pathology, generating an area under the curve (AUC) of 0.706 for NLR (95% CI, 0.535 - 0.876, p-value = 0.035) and 0.767 for PLR (95% CI, 0.615-0.918; p-value = 0.006); the optimal cut point by Youden’s index for NLR was 8.29 and 267.94 for PLR (Sensitivity: 76%, Specificity: 67%). In contrast, the group with infectious pathology, the AUC was 0.47 for NLR (p = 0.78) and 0.42 for PLR (p = 0.44). The relationship of the biomarkers with stay in ICU was also evaluated, finding a statistically significant association with the lactate value (p = 0.024, Kruskal-Wallis) Conclusions: Inflammatory markers are useful as predictive markers of mortality in critically ill patients due to non-infectious causes. The lactate value serves as a predictive factor of stay in the ICU for all the patients. We suggest carrying out prospective studies to confirm the validity of our findings.
The utility of circulating tumor DNA analysis to identify BRAF mutations in malignant melanoma.
Authors: Kirby Eric , Leming Philip D. 
Published: May 2019

e14539 Background: Circulating tumor DNA provides an opportunity to assess the genetic profile of a patient’s tumor without performing a tissue biopsy. The Guardant360 assay is one platform available to perform genetic sequencing of circulating tumor DNA from a blood sample. This can allow for assessing the BRAF mutation status of patients with malignant melanoma from a liquid biopsy. Methods: Retrospective chart review was done of patients with malignant melanoma with a positive BRAF V600 mutation based on a tissue biopsy. The BRAF V600 mutation status of these patents as determined by a Guardant360 assay, which was not necessarily done at the same time as the tissue biopsy, was gathered. The status of each patient’s malignancy at the time of each liquid biopsy was assessed and divided into three categories, which included active distant metastatic disease, active locoregional disease, and no evidence of active disease. Results: 51 total patients with a positive BRAF V600 mutation based on tissue biopsy were included in this analysis. Some patients had multiple Guardant360 assays which were done at different timepoints, which made for 83 total liquid biopsies. Out of 30 liquid biopsies done when the patient had evidence of active distant metastatic disease, 21 (70%) were positive for a BRAF V600 mutation. Out of 13 liquid biopsies done when the patient had evidence of active locoregional disease, 2 (15.4%) were positive for a BRAF V600 mutation. Out of 40 liquid biopsies done when the patient had no evidence of active disease, 3 (7.5%) were positive for a BRAF V600 mutation. Conclusions: The Guardant360 assay in detecting a BRAF V600 mutation had it’s highest sensitivity in the setting of active distant metastatic disease. This assay can allow for sparing patients more invasive tissue biopsies when the suspicion for metastatic melanoma is high and the BRAF mutation status is unknown.
REG4 as a novel biomarker of lung adenocarcinoma with mutated KRAS and TTF-1 low expression.
Authors: Yu Hui , Sun Si 
Published: May 2019

e14541 Background: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation coupled with low expression of the TTF-1 (KC subgroup). The aim of this study was to identify novel biomarkers through searching the candidate molecules that contributing to lung adenocarcinoma pathogenesis, especially KC subtype. Methods: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after the silencing REG4 expression. Results: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutated lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduce cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce the cell cycle arrest by regulating G2/M checkpoint and E2F targets. Conclusions: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanism of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.
Real-world application of liquid biopsy in gastrointestinal tumors: Experience from a comprehensive cancer center.
Authors: Sanz-Garcia Enrique , Rodriguez Laura , Alvarez-Gallego Rafael , Rodriguez-Pascual Jesus , Munoz Cesar , Ugidos Lisardo , Ceniceros Lucia , Boni Valentina , De Miguel Maria José , Almirall Cristina , Calvo Emiliano , Ayuso-Sacido Angel , Cubillo Gracián Antonio 
Published: May 2019

e14546 Background: Determination of circulating tumoral DNA (ctDNA) in plasma has recently emerged as an alternative to genomic testing in solid biopsy. Although different clínical trials have suggested that ctDNA alterations can tailor patient's treatment, its routinary utility in clinical practice is still controversial. Methods: A total of 74 consecutive plasma samples from 63 patients (pts) have been collected from October 2017 to December 2018 in our center and analyzed using two different next-generation sequencing (NGS) platforms: OncoTRACE (OT) and Guardant360 (G360). Main epidemiological, pathological and clinical data have been retrospectively extracted from medical records and correlation with ctDNA alterations have been performed using Chi-Square test. Application of liquid biopsy results has been decided after discussion in molecular tumor board and physician’s opinion. Results: OT and G360 were performed in 63 and 11 plasma samples respectively. Most part of the samples were from pancreatic (34; 45.9%) and colorrectal (CRC) (28; 25.7%) adenocarcinoma pts although biliary tract, gastric and oesophageal carcinoma pts were also included (4 each; 5.4%). Plasma samples were analyzed after progression to ≥two systemic therapies in 48.6%. At least one pathogenic alteration of ctDNA was detected in 44.6% of the samples. No correlation has been observed between presence of alteration in ctDNA and tumor origin, surgery of the primary, number and location of metastases and CEA and CA19.9. ctDNA alteration could be targetable with approved or experimental therapies in 14 pts (20.9%; 6 pts OT and 8 pts G360): 9 pts with CRC ( BRAF, EGFR, RAS, PI3KCA, PTEN), 2pts with pancreatic ( IDH1, BRCA1) and 1 pt with gastric, oesophageal and biliary tract carcinoma ( PTEN, EZH2, IDH1). However, these results have been applied in 4 pts (6% of all pts, 28.6% with targeteable ctDNA alterations): 3 pts were treatment-naïve and 1 pt had progressive disease to 2 systemic therapies. Most part of the patients with targetable alterations who did not receive treatment was due to clinical deterioration. Conclusions: Detection of alterations in ctDNA using NGS platforms is feasible in gastrointestinal tumor patients and can help physicians to decide treatment, especially in CRC. However, many patients could not be treated according to ctDNA as plasma samples were collected in late stages of the disease.
Analysis of AKR1B10 levels among various groups of breast cancer patients.
Authors: Rao Krishna A. , Robinson Kathy , Delfino Kristin , Tiwari Vivekanand , Zhu Yun , Wang Xin , McClintock Andrew , Bekker Simon , Westbrook Joshua , Cao Deliang , Cao Zhe 
Published: May 2019

e14548 Background: Aldo-keto reductase 1B10 (AKR1B10) is a protein that is primarily expressed in human colon and small intestine, but induced in hepatocellular carcinoma and non-small cell lung cancer. Our recent studies have revealed that AKR1B10 is overexpressed in primary, metastatic, and recurrent cancers of the breast. Methods: We recruited four cohorts of patients: Patients with breast cancer undergoing primary surgery from whom we procured breast cancer and matched normal adjacent tissue to evaluate AKR1B10 expression in primary tumors. The matched serum samples were collected before surgery and at various time points after the surgery (approximately 3 days, 7 days, and 1 month Patients with recurrent or advanced (metastatic) breast cancer. Serum samples were collected and serially monitored for up to 2years before and during metastatic therapy and correlated with RECIST measurements. Patients with locally advanced disease undergoing neoadjuvant chemotherapy. AKR1B10 serum levels were monitored during therapy and correlated with RECIST measurements. Healthy individuals with normal mammograms were recruited and submitted serum samples for AKR1B10 serum measurements. Results: AKR1B10 rapidly cleared the serum of early stage breast cancer patients with an estimated half-life of 24-30 hours. Serum AKR1B10 levels correlated strongly with tissue IHC staining and PR positivity but not with RECIST levels or Oncotype Dx scores. Neoadjuvant chemotherapy did not affect serum AKR1B10 levels. Individuals with normal mammograms displayed substantially lower levels of AKR1B10 than breast cancer patients. Patients with DCIS also displayed elevated serum AKR1B10 levels. Conclusions: AKR10 may serve as tumor marker to independently identify high risk patients whose tumors have intermediated risk Oncotype Dx scores and may also identify early breast cancers in patients with equivocal breast biopsies.
Detection of circulating cancer stem cells (cCSCs) as a predictive biomarker for breast cancer relapse or metastasis.
Authors: Pizon Monika , Pachmann Ulrich A. , Pachmann Katharina , Schott Dorothea 
Published: May 2019

e14559 Background: Breast cancer is one of the most common types of cancer in women worldwide. It has been demonstrated that even localized tumors without clinically apparent metastases give rise to circulating epithelial tumor cells (CETCs). Recent studies have provided strong support for the cCSC hypothesis, which suggests that a more aggressive subpopulation of circulating tumor cells is the source of metastatic spread from the primary tumor. Measuring CETCs in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers. However, accurate detection of CETCs may provide erroneous results, since CETCs undergoing EMT during metastasis are down-regulated for the expression of epithelial cell markers. Methods: 26 breast cancer patients were included into the study. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. Cell viability, surface marker expression and ALDH 1 activity of the cells in the spheres were evaluated by fluorescence scanning microscope. Results: Sphere formation was observed in 80 % of patients. We found that the number of tumorspheres depended on stage of disease. The number of tumorspheres increased significantly with tumor progression, especially with the presence of metastases. Tumorsphere formation was observed in all metastatic patients (median of 30 tumorspheres/100µl of blood), although only 27% of them had detectable CETCs. Analysis of surface marker expression profile showed that the cells in the spheres had typical phenotype of cancer stem cells. Sphere formation was not observed in healthy subjects (n = 20). Conclusions: There is a high correlation between the numbers of tumorspheres cultured from peripheral blood with clinical stage of disease. Identifying cCSC in blood sample can help clinicians to monitor breast cancer patients and to detect metastasis in early stages.
Use of a clinical trials screening tool in the NCI Community Oncology Research Program (NCORP) to enhance accrual and promote disparities research.
Authors: St. Germain Diane C. , Budd Troy , McCaskill-Stevens Worta J. 
Published: May 2019

e14587 Background: Despite the identification of multiple patient, clinician, and health systems barriers, accrual to a new generation of cancer clinical trials continues to present challenges. It may be that barrier data is not sufficiently granular. A clinical trial screening tool was developed for use in NCORP to collect trial- and site-specific information as well as broadened demographic data to determine factors that may impact accrual. Methods: The tool was developed with stakeholder input and the NCI Oncology Patient Enrollment Network was used for data input and analyses. Results: From February 2016 to December 2019, 14,340 entries were made in the screening tool. Eighty-two percent of participants consented to participate. Participants screened were female (77%), married (64%) and Caucasian (85%). Fourteen percent of the participants were racial minorities (1% not reported) and 5% were Hispanic or Latino. The mean age was 60 (range 1-95). Thirty-six percent were employed, ≥ 32 hours per week followed by 35% retirees. Income did not vary significantly ( < $25,000(16%), $25,000 - $50,00 (20%), $51,000 - $10,000 (26%), and > $100,000 (19%), and 19% of participants refused to provide income data. Four percent of the participants were uninsured at diagnosis. Seventy-two percent (8,501) of participants screened enrolled in a clinical trial. Of those not enrolled, 49% were ineligible and 48% were eligible but declined to participate. The most common reasons for ineligibility included concurrent disease, abnormal lab or other tests, and patient could not comply with eligibility criteria. The most common reasons eligible participants declined to participate were perception that toxicities were too great and social issues (child care, transportation). Further analysis of the data will include correlation of race/ethnicity, age, income and co-morbidities with enrollment status. Conclusions: The majority of participants approached agreed to participate in the screening tool protocol. Approximately half of the participants were eligible for a trial but declined to participate. These issues will be addressed within the network to enhance accrual. The data collected will also provide opportunities for investigators within the network to develop research questions focused on disparities and clinical trial accrual.
The ACC melanoma pilot project: “Real-world” evaluation of an NGS platform for molecular characterization of melanoma in Italy.
Authors: Molineris Ivan , Levati Lauretta , Berrino Enrico , D'Atri Stefania , Menin Chiara , Madonna Gabriele , Bulgarelli Jenny , Ghiorzo Paola , Ferraresi Virginia , Venesio Tiziana , Rivoltini Licia , Rodolfo Monica , Lanfrancone Luisa , Mazzarella Luca , Guida Alessandro , Pelicci Pier Giuseppe , De Maria Ruggero , Ascierto Paolo Antonio , Medico Enzo , Russo Giandomenico ,   Alliance Against Cancer-Working Groups: Melanoma, Genomics, Pathology
Published: May 2019

e14600 Background: Alliance Against Cancer (ACC), the network of Italian Cancer Centers, is involved in designing targeted NGS panels to enable sequencing a significant number of therapeutically actionable genes from FFPE tissue samples at the cost of a routine molecular diagnostic test (RMT). In this retrospective study we used the ACC oncochip v.1 on a cohort of stage III-IV metastatic melanoma patients, with the aim of: a) validating the diagnostic use of this oncochip in comparison with RMTs for BRAF mutation detection; b) evaluating how many additional actionable gene mutations can be identified per patient; c) evaluating possible associations between mutational profiles and outcome. Methods: DNA was extracted from 120 FFPE samples from 9 Italian hospitals previously profiled for BRAF status with a RMT, and matching germline samples. 60% of the patients underwent immunotherapy and 40% targeted therapy, with an overall survival ranging from few days to several years. 10-20 ng of DNA were profiled with the amplicon-based ACC Oncochip v.1, that covers ~700 Kb, including the full coding sequence of 182 genes. Samples were sequenced in a Ion Torrent S5 instrument (ThermoFisher), and mutational profiles were generated with the Ion Reporter software. Results: Adequate coverage of the BRAF codon 600 hotspot was reached in 99% of the samples, and BRAF status was 95% concordant with previous RMTs. In 4/6 discordant cases, BRAF V600 mutations were only detected by NGS (with VAF below 10%); in the remaining two cases NGS did not confirm mutations detected by RMT, possibly due to tumor heterogeneity. In accordance with TCGA data, BRAF was mutated in 55% of patients, NRAS in 23% and NF1 in 13%, with almost complete mutual exclusivity; moreover 86% of triple negative patients showed mutations in other actionable genes. We also observed great variability in mutational load, ranging from ~3 to > 500 somatic mutations per Mb; correlation between mutational profiles and clinical outcome is underway. Conclusions: The ACC Oncochip v.1 NGS panel is accurate and affordable, providing a comprehensive mutational profile for the cost of a RMT and allowing a precision medicine approach to melanoma diagnosis and identification of actionable mutations.
Validation and utilization of NGS based HEMEaccuTest panel and analysis software for hematological malignancies.
Authors: Choi Hyun-Jeung , Lee In-seon , Lee Min Kyoung , Im Ji-Eun , Jung Kyongyong , Lee Keunsook Kathy , Moon YoungJoon , Kim Kwang Joong 
Published: May 2019

e14606 Background: Hematological malignancies are forms of cancer that originate in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Hematological malignancies can be classified as leukemias, lymphomas, multiple myeloma (MM), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) based on the cell type where they originate. Detection of genetic alteration in hematological malignancies is increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is an advanced technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related for clinical diagnostics. Methods: We developed the targeted NGS panel, HEMEaccuTest and automatic analysis software, NGeneAnalySys for estimating the relative pathogenicity of hematological malignancies. HEMEaccuTest covers about the 310 kilobases with exon regions of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. the diagnostic utility of the panel and software were validated using genotype-known reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600x and a minimum coverage depth of 100x. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity and specificity of the panel were high in a comparison to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by an excellent simulating algorithm of NGeneAnalySys. Conclusions: This analytical validation demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent tool for disease definition and therapeutic strategy in hematological malignancies.