bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating cell-free tumor DNA chromosomal instability and circulating tumor cells as tools to predict microvascular invasion of hepatocellular carcinoma.
Authors: Wang Jin , Liu Yanzhe , Chen Kuang , Liu Qu , Ziliang Qian , HU Minggen 
Published: May 2019

e14524 Background: Extended hepatic surgical margins, especially anatomical resections, were suggested for hepatocellular carcinoma (HCC) patients with pathological microvascular invasion (MVI) to improve patient survival. Here we investigated plasma cell-free tumor DNA (ctDNA) and circulating tumor cells as a tool to evaluate MVI before surgery. Methods: 47 treatment-naïve patients with liver lesions were recruited since June 2018, Peripheral blood samples were collected before surgery for all the individuals. Plasma cfDNA was sent to low-coverage genome-wide sequencing, followed by chromosomal instability analyses by a customized workflow UCAD. Circulating tumor cells (CTC) were analyzed by CELLSEARCH@ System. MVI was reported by pathological examination after surgery. Results: Of the 47 patients recruited, there are 32 hepatocellular carcinoma (HCC), 8 intrahepatic cholangiocarcinoma (ICC), 4 benign lesions, 1 solitary fibrous tumor, 1 neuroendocrine tumor and 1 hepatic epithelioid cell tumor by pathological examinations. MVI was also reported for HCCs. Nineteen of 32 HCC patients (59.4%) was found with elevated chromosomal instability (CIN). The most frequent changed chromosomes include 1q, 6p and 8q. Nine of 19 (47.4%) elevated CIN patients were MVI positive by pathological examinations. Among them, 4 was confirmed as MVI = 2. The other 5 was MVI = 1. 11 of 13 (84.6%) patients with low CIN were MVI negative (MVI = 0) as reported by pathological examinations. The rest 2 were reported as MVI = 1. Two of 32 HCC patients (6.25%) was found with positive CTC (tumor cell count > 0). The patient with CTC = 2 was reported as MVI = 1. The other one with CTC = 1 was MVI = 0. Taking together, 20 patients (62.5%) were found either elevated ctDNA or positive CTC. 9 were confirmed as MVI negative. The overall positive predictive value is 45.0%. 12 patients (38.7%) were both ctDNA CIN low and CTC negative. 10 were confirmed as MVI negative. The negative predictive value (NPV) is 83.3%. Conclusions: Elevated circulating tumor DNA chromosomal instability has good PPV and NPV in the predicting of MVI. In such patients, anatomical hepatic resections might be recommended to improve survival.
Zero delay plasma vs. Streck cfDNA tubes: Does immediately centrifuging blood at the point of draw improve cell-free DNA signal-to-noise?
Authors: Sommer Greg , Fredriksen Laura , Iacovetti Gabriella , Hong Kyungjin , Schaff Ulrich 
Published: May 2019

e14529 Background: Sample quality is a critical consideration for high fidelity cell-free DNA (cfDNA) testing. Oncological cfDNA tests used for liquid biopsy typically employ specialty blood collection tubes containing chemical preservatives to minimize degradation of samples prior to lab testing. Here we describe a newly developed device, Zero Delay Plasma– a portable centrifuge and disc system designed to immediately isolate cell-free plasma at the point of blood draw – and evaluate its performance against the Streck cfDNA collection tube. Methods: Whole blood was collected, processed, and stored at room temperature for up to 7 days with both the Zero Delay Plasma system and the Streck cfDNA blood collection tube. Sample hemolysis was measured via cell-free hemoglobin. Genomic contamination and cfDNA signal-to-noise were evaluated by qPCR and electrophoresis, comparing signal from target 150-200bp cfDNA to contaminating longer length genomic sequences in the sample. 2 sets of hemolysis experiments, 2 sets of electrophoresis experiments and 4 sets of qPCR experiments were conducted. Results: Plasma processed with the Zero Delay Plasma system yielded ~4X lower hemolysis levels, ~10X lower genomic contamination, and ~20X higher cfDNA signal-to-noise compared to the Streck cfDNA collection tube after 7 days of storage at room temperature. Conclusions: The Zero Delay Plasma system minimizes sample degradation and analytical background signal for cfDNA testing by immediately removing cells and other contaminants at the point of blood collection. Clinical evaluations are in process.
Assessing the impact of clonal hematopoiesis in disease monitoring using targeted cell-free DNA (cfDNA) sequencing technology.
Authors: Yaung Stephanie J. , Xi Liu , Woestmann Corinna , Ju Christine , Klass Daniel M. , Casey Fergal , Hinzmann Bernd , Heussel Claus Peter , Thomas Michael , Herth Felix , Muley Thomas , Wehnl Birgit , Palma John F. , Ma Xiaoju Max 
Published: May 2019

e14530 Background: Somatic variants found in plasma cell-free DNA (cfDNA) may derive from either solid tumors or clonal hematopoiesis (CH). Little is known about how this may impact plasma-based longitudinal disease monitoring using targeted sequencing of circulating tumor DNA (ctDNA). Methods: To assess the potential impact of CH in disease monitoring, we evaluated monitoring algorithms by targeted sequencing with and without matched peripheral blood mononuclear cells (PBMC). Samples were collected from a prospective observational study, where 62 late stage lung adenocarcinoma subjects were treated with first-line chemo or chemoradiation therapy. Pre-treatment plasma cfDNA and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a sequencing panel of 198 kilobases targeting cancer genes. Median input amounts of 25 ng cfDNA and 50 ng PBMC DNA were sequenced to median deduplicated depths of 4582 and 6134, respectively. Results: A median of 120 single nucleotide variants were detected per cfDNA sample, with 93.1% of these identified in matched PBMC. Most PBMC-matched cfDNA variants were germline SNPs, with allele frequency (AF) ~ 50% or 100%. A median of 1 (range 0-5) PBMC-matched cfDNA variants per sample were detected with an AF < 10%, consistent with CH. The number of these variants was positively associated with age (p-value = 0.0039) and the most frequently mutated gene was TP53. The remaining somatic variants (i.e., in cfDNA and not PBMC) had an AF range 0.03-40.9%. These PBMC-informed variants (median of 7 per sample) were used in longitudinal monitoring in the first post-treatment plasma sample to assess early response to therapy. Association between ctDNA level and progression-free survival using the same monitoring algorithm yielded nearly identical results on somatic variants derived from filtering approaches independent of matched PBMC (HR 0.32; 95% CI 0.16 - 0.65; log-rank P = 0.0009) and the PBMC-informed method (HR 0.31; 95% CI 0.14 - 0.66; log-rank P = 0.0013). Conclusions: A targeted panel focused on solid tumors by design has limited impact from CH. For disease monitoring applications in a non-MRD setting, measuring multiple variants instead of a single variant further enables robust classifiers that can moderate the impact of variants, if any, from CH.
CTC enumeration and characterization as a pharmacodynamic marker in the phase I clinical study of APX3330, an APE1/Ref-1 inhibitor, in patients with advanced solid tumors.
Authors: Chu Lincy , Anderson Amanda K. L. , Landers Mark Andrew , Wang Yipeng , Kelley Mark R. , Messmann Richard Adam 
Published: May 2019

e14531 Background: APE1/Ref-1 is a dual-function protein with a pleiotropic role in regulating transcription factors involved in cancer cell signaling via redox control, as well as responding to oxidative and base DNA damage. APX3330 is a highly selective inhibitor of the Ref-1 mediated redox function in tumors, while enhancing the neuronal protective function of APE1. APX3330 is undergoing clinical development as an anti-tumor agent that also protects and reverses oxidative damage to neurons. We now report on the CTC analysis conducted as part of the study (NCT0337508). Results of the clinical study are reported in a separate abstract. Methods: A total of 19 patients with 10 various solid tumors, including rectal, pancreatic, colon, endometrial, gall bladder, hepatocellular, prostate, melanoma, bladder, and ovarian cancers received APX3330 in escalating divided daily doses of 240, 360, 480, 600, and 720mg. Blood samples were collected from all patients prior to receiving APX3330 and after achieving steady-state serum concentrations of the drug. Samples were sent to Epic Sciences to analyze circulating tumor cells (CTCs) in peripheral blood via their CTC Platform. Results: Cumulatively, 37 samples from 19 patients were received. 35/37 (95%) samples passed technical quality control and were feasible for downstream analysis. 9/17 (53%) baseline samples (BL) had CTCs detected, while 9/18 (50%) on-treatment (OTx) draws had CTCs detected. 16 patients had BL and OTx samples that were further evaluated with the longitudinal analysis. Of these, 7/16 (44%), 6/16 (38%), and 3/16 (19%) patients showed a reduction trend, an increase trend, and no change in all CTC populations (delta greater than or equal to 0 CTC/ml), respectively. Patient follow-up is ongoing and the correlation of CTC biomarkers with clinical outcomes is pending. Conclusions: APX3330 is undergoing clinical evaluation as an anti-tumor agent that protects against and reverses CIPN. In this phase I study, 44% of evaluable blood samples showed a reduction in CTCs after initiation of treatment with APX3330. Additional studies are now being planned. Clinical trial information: NCT0337508.
Follow-up evaluation of outliers with elevated spermine-spermidine acetyltransferase-1 activity.
Authors: Maksymiuk Andrew W. , Tappia Paramjit S. , Ramjiawan Bram , Khatun Nazrina , Parveen Rahnuma , Ahmed Rashiduzzaman , Huang Gina , Bux Ahmed Rashid , Akhtar Parveen S. , Bach Horacio , Sitar Daniel 
Published: May 2019

e14536 Background: In the evolving role of biomarkers, proteinomic signatures related to up-regulation of polyamine synthesis including spermine/spermidine acetyltransferase-1 (SSAT-1) appear to be promising markers of malignancy. Acetylamantadine (AA) excretion, a measure of SSAT-1 up-regulation, has been shown to be a marker for malignant proliferation. In preliminary analyses of ostensibly normal individuals from Canada (Winnipeg) and Bangladesh (Dhaka), a proportion were identified to have evidence of SSAT-1 up-regulation above the expected non-malignant range (outliers). These outliers were assessed and followed for development of identifiable medical conditions. Methods: SSAT-1 up regulation was assessed in 60 ostensibly normal individuals by analysis of urinary excretion of AA after ingestion of amantadine 200 mg x 1 dose. AA was assayed using HPLC-mass spec techniques as previously described. Outliers who consented were followed-up by clinical examinations, routine biochemical and hematological tests and radiographs, where indicated. Results: Total AA average (median) excretion at 6 hrs in the Winnipeg cohort was 579+/-252 vs 1699+/-633 ng in the Dhaka cohort. Average urinary concentration at 6 hrs was 3.75+/-0.75 vs 21+/-20 ng/ml. In outliers consenting to follow-up, 1 case of invasive malignancy was identified, 6 cases of pre-malignant neoplastic change, chronic liver disease in 7 cases and chronic inflammation in 2 cases. In others, no malignant or inflammatory conditions have yet been identified. The range of SSAT-1 activity in individuals living in Bangladesh was significantly higher than in the Canadian cohort. Bangladesh volunteers live in an area of known to have high natural contamination with arsenic, a recognized carcinogen and they are exposed to high levels of air pollution. Conclusions: By this assay, high SSAT-1 activity has been confirmed in patients harbouring malignancy; however, pre-malignant and inflammatory conditions may result in a positive test. Follow-up of individuals with elevated SSAT-1 activity may reveal unrecognized malignancies, pre-malignant neoplasms, liver disease, inflammatory conditions and possibly false-positivity in individuals exposed to carcinogens such as arsenic. In further work, SSAT-1 up-regulation is being correlated with 5 other putative polyamine metabolite markers for accurate diagnosis of lung cancer.
Functional cell profiling (FCP) of ~100,000 CTCs from multiple cancer types identifies morphologically distinguishable CTC subtypes within and between cancer types.
Authors: Vansant Gordon , Jendrisak Adam , Sutton Ramsay , Orr Sarah , Lu David , Schonhoft Joseph , Wang Yipeng , Dittamore Ryan 
Published: May 2019

e14553 Background: Different cancers subtypes can often be effectively treated with similar Rx classes (i.e. platinum or taxane Rx). Yet, within a disease patient therapy benefit can be variable. The origins of precision medicine derive from pathologic sub-stratification to guide therapy (e.g. SCLC vs. NSCLC). Using the Epic Sciences platform, we performed FPC analysis of ~100,000 single CTCs from multiple indications and sought to utilize high resolution digital pathology and machine learning to index metastatic cancers for the purpose of improving our understanding of therapy response and precision medicine. Methods: 92,300 CTCs underwent FCP analysis (single cell digital pathology features of cellular and sub-cellular morphometrics) were collected from prostate (1641 pts, 70,747 CTCs), breast (268 pts, 8,718 CTCs), NSCLC ( 110 pts, 1884 CTCs), SCLC ( 141 pts, 8,872 CTCs) and bladder (65 pts, 2079 CTCs) cancer pts. After pre-processing the raw data, a training set was balanced by sampling the same number of CTCs from each indication. K-means clustering was applied on the training set and optimized number of clusters were determined by using the elbow approach. After generating the clusters on the training set, the cluster centers were extracted from k-means, and used to train a k-Nearest Neighbor (k-NN) classifier to predict the cluster assignment for the remaining CTCs (test set). Results: The optimized # of clusters was 9. The % and characteristics of CTCs in each indication are listed below. BCa CTCs were more enriched in cluster c1, which had higher CK expression, while SCLC and some of mCRPC shared the small cell features (c5). Conclusions: Heterogeneous CTC phenotypic subtypes were observed across multiple indications. Each indication harbored subtype heterogeneity and shared clusters with other disease subtypes. Patient cluster subtype analysis to prognosis and therapy benefit are on-going. Analysis of linking of CTC subtypes genotypes (by single cell sequencing) and to patient survival on multiple indications is ongoing.[Table: see text]
RNA-based biomarker signatures in plasma as an independent predictor of outcome to chemotherapy in lung, colon, and breast cancers: Correlation of relative PD-L1 expression with immunotherapy outcomes.
Authors: Raez Luis E. , Usher Joshua L. , DANENBERG KATHLEEN , Sumarriva Daniel , Castrellon Aurelio Bartolome , Rabizadeh Shahrooz , Milillo Adriana , Hunis Brian , Reddy Sandip , Huang Liyang , Zikria Jennifer , Ferraro Pablo , Danenberg Peter 
Published: May 2019

e14567 Background: Levels of cell-free circulating RNA (cfRNA) in cancer patients (pts) indicate tumor gene expressions and thus may provide a means, not only of evaluating response, but also for monitoring and predicting outcome to therapy. Methods: Blood was drawn every 6-8 weeks from pts undergoing various treatments (tx). CfRNA was extracted from resulting plasma and generated random-primed cDNA. Total cfRNA was quantitated by qPCR of β-actin, and correlated with pts response (CR/PR/SD/PD) determined by CT scans. Changes in PD-L1 expression were used to monitor response to immunotherapy in lung cancer pts. 125 pts (50 lung, 51 breast, 24 colon) were enrolled. Among the three tumor types, a total of 84 pts completed 1-3 lines of tx with an average of 5 blood draws per pt. Results: Changes in total levels of cfRNA over time correlated with pts outcomes in all three tumor types and were independent of the specific therapies. Increasing (INC) levels of cfRNA were predictive of disease progression and decreasing (DEC) levels with benefit from therapy, with an overall concordance of 81% (68/84 pts). Changes in relative PD-L1 expression were associated with immunotherapy outcomes in lung cancer (INC associated with progression, DEC associated with benefit). Lung: There was a 79% (23/29) concordance between changes in cfRNA levels and pts response. Changes in relative PD-L1 expression were predictive of outcome to immunotherapy in 9/10 pts. Breast: There was an 83% (30/36) concordance between cfRNA levels and pts response. Colon: There was a 79% (15/19) concordance between cfRNA levels and pts response. Conclusions: A noteworthy concordance was observed between clinical response and changes in cfRNA levels in lung, breast and colon cancer pts, independent of chemotherapy regimen. Changes in relative PD-L1 gene expression correlated specifically with outcome to immunotherapy (90%). We conclude that changing cfRNA levels can indicate tx response, and PD- L1 could be used to monitor response to immunotherapy.
Tracking circulating cell-free tumor DNA in gastric cancer to detect early disease recurrence.
Authors: Yang Jian , Gong Yuhua , Lam Vincent K. , Shi Yan , Guan Yan-Fang , Zhang Yanyan , Ji Liyan , Chen Yongsheng , Zhao Yongliang , Qian Feng , Chen Jun , Li Pingang , Zhang Fan , Wang Jiayin , Yang Ling , Futreal Andrew , Zhang Jianjun , Yi Xin , Xia Xuefeng , Yu Peiwu 
Published: May 2019

e14571 Background: Identifying locoregional gastric cancer patients who are at high risk for relapse after resection could facilitate early intervention. By detecting molecular residual disease (MRD), circulating tumor DNA (ctDNA) has been shown to predict post-operative relapse in several cancers. Here, we aim to evaluate MRD detection by ctDNA and its association with clinical outcome in resected gastric cancer. Methods: This prospective cohort study enrolled 46 patients with stage I-III gastric cancer that underwent resection with curative intent. Resected tumor samples and plasma samples were obtained for targeted deep sequencing and longitudinal ctDNA profiling. Results: ctDNA was detected in 45% of treatment-naïve plasma samples. T stage was independently associated with pre-operative ctDNA positivity (p = 0.006). All patients with detectable ctDNA in the immediate post-operative period eventually experienced recurrence. ctDNA positivity at any time during longitudinal post-operative follow-up was associated with worse DFS and OS (HR = 14.78, 955 CI, 7.991-61.29, p < 0.0001 and HR = 7.664, 95% CI, 2.916-21.06, p = 0.002, respectively), and preceded radiographic recurrence by a median of 6 months. Conclusions: In locoregional gastric cancer patients treated with curative intent, these results indicate that ctDNA-detected MRD identifies patients at high risk for recurrence and can facilitate novel treatment intensification studies in the adjuvant setting to improve survival.
The host response to immune checkpoint inhibitors: From mechanisms to therapeutic implications.
Authors: Fremder Ella , Jacob Eyal , Khononov Irena , Issler Eran , Raveh Shani , Dahan Nili , Bar Haim , Shaked Yuval 
Published: May 2019

e14584 Background: One of the major challenges in clinical immuno-oncology today is predicting which patients will respond to treatment. Although the use of immune checkpoint inhibitors (ICIs) has significantly improved therapeutic outcomes in a subset of patients with advanced malignancies, the majority of patients do not respond to treatment and some even hyper-progress. This response pattern raises questions regarding the possible mechanisms of resistance to ICIs. In the last decade we and others have shown that the host, in response to almost any type of anti-cancer drug, generates pro-tumorigenic and pro-metastatic effects which in turn contribute to tumor relapse and resistance to therapy despite an initial response. However, such host effects have never been investigated using immune-oncology drugs. Methods: We used functional and computational methods on plasma samples from both mouse models and cancer patients to identify the host-mediated tumor promoting molecular pathways that are induced in response to ICI therapy. Results: We found that these pathways are composed of dominant factors that regulate pro-inflammatory, metastatic and proliferation activities and thus contribute to rapid tumor re-growth. In pre-clinical models, we have found that pharmacological blockade of specific dominant factors overcomes the tumor-promoting effects induced by the host in response to ICI therapy. Conclusions: Based on our collective findings, we propose that therapies inhibiting host-mediated pro-tumorigenic effects could be used in combination with ICIs as a strategy to minimize tumor hyper-progression and increase the susceptibility of resistant tumors to ICI therapy. Furthermore, our studies pave the way towards the discovery of new predictive biomarkers for identifying subjects who will benefit from ICI therapy.
Prognostic value of serum apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) ratio in hepatocellular carcinoma patients with transcatheter arterial chemoembolization treatment: propensity score-matched analysis.
Authors: Liu Meng meng , Chen Zhan-Hong , Chen Yu-tong , Wang Zi-xian , Wu Xiangyuan , Dong Min 
Published: May 2019

e14589 Background: The aim of our research was to assess the prognostic value of ApoB to ApoA-I ratio (ApoB/ApoA-I) in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) treatment. Methods: We collected clinicopathological data of 455 HCC patients with TACE treatments. The cutoff value of ApoB/ApoAI identified by receiver-operating curve (ROC) was 0.56. Correlation analysis was carried out to explore the relationship among ApoB/ApoA-I and other clinicopathological variables. Propensity score-matched (PSM) analysis was carried out to eliminate the unbalance of baseline characteristics of high and low ApoB/ApoA-I group. Finally, 278 patients were included in the PSM cohort, 139 patients in the high APOB/APOA-I group and 139 patients in the low APOB/APOA-I group. Univariate and multivariate analysis were conducted to explore the independent prognostic value of ApoB/ApoA-I in 455 patients and in the PSM cohort. Results: ApoB/ApoA-I was significantly correlated with AFP, NCCN T stage, distant metastasis status and TNM system(P < 0.05). Patients with AFP≥400ng, T3-4, distant metastasis and TNM III-IV had significantly higher serum ApoB/ApoA-I level than that of patients with AFP ≥ 400 ng/ml, T1-2, without metastasis and TNM I-II(P <0.05). Patients in high ApoB/ApoA-I group had significantly shorter overall survival compared to those in low ApoB/ApoA-I group in 455 HCC patients and in the PSM cohort (P < 0.01). Multivariate analysis indicated that ApoB/ApoA-I was an independent prognostic index for OS in 455 HCC patients and the PSM cohort (HR = 1.443, P = 0.006; HR = 1.564, P = 0.006, respectively.) Conclusions: Serum ApoB/ApoA-I is a novel independent prognostic factor for the HCC patients treated with TACE.