bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone metastasis unique plasma exosomal microRNA signature in non-small cell lung cancer.
Authors: Pi Can , Yu Ruoying , Peng Xiaoxiao , Zhang Xuchao , Chen Zhihong , Wu Xue , Fan Xiaojun , Shao Yang , Zhou Qing 
Published: May 2019

e14534 Background: 20-40% of lung cancer patients develop bone metastasis (BM) with significantly decreased overall survival. Currently, BM is mainly diagnosed by CT scan or MRI when symptom develop. Novel biomarkers with higher prediction value of BM are needed. Tumor secreted exosomes that are enriched with microRNAs have been recently implicated in site-specific tumor metastasis for establishing a distant pro-metastatic niche. Methods: Plasma exosomes from 39 stage IV non-small cell lung cancer (NSCLC) patients (n = 23 with BM; n = 16 without BM) and 16 healthy individuals were separated by ultracentrifugation. Total RNAs were extracted followed by small RNA-sequencing. miRNA identification was performed by miRDeep2. Weighted correlation network analysis (WGCNA) was used for identifying co-expression networks of highly correlated miRNA clusters. miRNA enrichment analysis and annotation (MIEAA) was applied for pathway analysis. Differential expression of individual miRNA was analyzed by edgeR. Results: Hierarchical clustering based on the total miRNA profile can clearly separate cancer patients and healthy individuals (HP), but not patients with (BM+) or without (BM-) BM. WGCNA identified three consensus clusters (A, B, C) of highly correlated miRNAs, among which cluster A (144 miRNAs) showed significantly differential expression in lung cancer patients, especially in BM+ group. Pathway analysis of cluster B miRNAs revealed enrichment in glycolysis and gluconeogenesis pathways that may involve in metabolic preconditioning of the metastatic niche. Three differentially expressed miRNAs between BM+ and BM- patients within cluster A were identified as miR-574-5p, a suppressor of Wnt/β-catenin pathway, was down-regulated, while miR-328-3p and miR-423-3p, two activators of the same pathway, were up-regulated in BM+ patients. Cluster B miRNAs (n = 49) also showed trend of upregulation in BM+ patients. Interestingly, pathway analysis indicated that 43 of them are associated with chr14, which has been suggested to promote EMT and bone metastasis. Conclusions: NSCLC patients with BM displayed unique plasma exosomal miRNA profiles, which might involve in promoting BM, and be potential biomarkers for predicting BM in NSCLC.
Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Authors: Ghidini Michele , Hahne Jens Claus , Senti Chiara , Lampis Andrea , Ratti Margherita , Pizzo Claudio , Gobbi Angela , Tomasello Gianluca , Passalacqua Rodolfo , Valeri Nicola 
Published: May 2019

e14545 Background: Liquid biopsies (LB) allow monitoring of genetically different and co-occurring cancer cell clones present in primary tumor and all metastatic sites in parallel. In metastatic colorectal cancer (mCRC), circulating-free DNA (cfDNA) can be relevant for monitoring treatment and identification of molecular alterations resulting in disease relapse often earlier than radiological examinations. Methods: Patients with mCRC at diagnosis and treated with chemotherapy (CT) in combination with antibodies (bevacizumab, cetuximab or panitumumab) before undergoing surgery for resectable disease were included in this study. LB were collected before therapy start, every four weeks during treatment, within ten days of radiological disease evaluation, at radiological relapse and until two months after relapse. Next generation sequencing based on plasma samples was performed (testing for mutations and copy number variations covering 77 genes). Results: From February 2016 to October 2018, 14 patients having surgery after first line treatment were included herein; median follow-up was 21.5 months. Five of them had RAS wild-type disease and received CT plus anti-EGFR treatment, while nine RAS mutated mCRC patients received bevacizumab. Surgery was radical in 10 cases, with no further treatment. In four cases, surgery was not radical and required further treatment. Disease relapse happened in seven cases, with subsequent death in three cases. In six out of seven cases, gene alterations were already detected in the pre-operative cfDNA. In the seven cases without disease relapse, gene variants were detected even after the surgery in two patients despite receiving radical resection. Median number of gene variants was two. Beside the well-established mutations in TP53 gene, both APC and ROS1 gene mutations were frequent, while further evaluations are required for the other variants detected. Conclusions: Evaluation of cfDNA mutations in LB from mCRC may be a useful tool for monitoring clinical response and predict treatment outcome. Moreover, this molecular analysis can help to subgroup patients with regard to risk of relapse after radical surgery. Indeed, cfDNA mutations present before surgery seem to be an indication for a higher risk of post-surgery disease relapse.
Precise prediction of the radiation pneumonitis with RPI: An explorative preliminary mathematical model using genotype information.
Authors: Du Lehui , Qu Baolin , Liu Fang , Ma Na , Xu Shouping , Yu Wei , Dai Xiangkun , Huang Xiang 
Published: May 2019

e14569 Background: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity and is one major obstacle for the radiotherapy of lung cancer. Reliable predictive factors or methods are strongly demanded by radiation oncologists. The purpose of this study is by determining the effectiveness of both genetic and non-genetic factors on their impact on the development of RP, to develop a clinically practicable approach for the risk assessment of RP. Methods: One hundred eighteen lung cancer patients who received radiotherapy were enrolled. RP events were prospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE4.0). Seven hundred thousand single-nucleotide polymorphism (SNP) sites of each patient were tested via Generalized Linear Models via Lasso and Elastic-Net Regularization (GLMNET) to determine their synergistic effects on the risk of grade≥2 RP prediction. Non-genetic factors including patient characteristics and dosimetric parameters were separately assessed by statistic test for their association with the risk of grade ≥2 RP. Based on the results of the aforementioned analysis, a multiple linear regression model named Radiation Pneumonitis Index (RPI) was built, for the assessment of grade ≥2 RP risk. Results: No statistically significant association were found between the RP risk (grade ≥2) and any of the non-genetic factors. Twenty five effective SNPs for predicting the grade≥2 RP risk were discovered and their coefficients of the synergistic effect were determined. An RPI score defined only by the information about these 25 SNPs can successfully distinguish the grade ≥2 RP population with 100% specificity and 97.8% accuracy. Conclusions: Non-genetic factors including important dosimetric parameters may not play dominant roles in the development of RP. Genotype information alone can effectively predict the risk of grade ≥2 RP. The combination of genetics and mathematical algorithms can be a new direction for radiotherapy in the field of precision medicine.
Characteristics of preceding trials associated with the outcome of subsequent phase III (P3) trials of targeted and immunological therapies in advanced cancers.
Authors: Lawrence Nicola Jane , Martin Andrew James , Roncolato Felicia , Tang Monica , Stockler Martin R. 
Published: May 2019

e14576 Background: Decisions to conduct P3 trials are based on evidence of activity from preceding trials. We sought the characteristics of preceding trials that were associated with a positive outcome in subsequent P3 trials of targeted and immunological therapies in oncology. Methods: We identified P3 trials of targeted and immunological therapies in advanced, solid-organ malignancies published from 2005 to 2015, and the preceding trials that were cited as their justification. We extracted characteristics and outcomes of the preceding trials and the subsequent P3 trials. We performed univariable and multivariable analyses to identify characteristics of preceding trials that were associated with a positive outcome in P3 trials. Results: We included 205 P3 trials with 542 citations of preceding trials. The experimental agent evaluated was (P3 trial, preceding trial respectively): small molecule (47%, 39%), immunotherapy (10%, 16%), monoclonal antibody (28%, 32%), hormonal therapy (7%, 6%), and other agent (8%, 6%). The primary endpoint was positive in 40% of P3 trials. The findings of preceding trials were reported ‘positively’ by their authors in 87%, but a priori criteria for judging their findings ‘positive’ were specified in only 74%, and met in only 53%. Characteristics of preceding trials that were associated with a positive primary endpoint in the subsequent P3 trial on multivariable analysis were: conduct in the same tumour type (odds ratio 2.35, 95% CI 1.0 to 5.6, p = 0.05), and sponsored by industry (odds ratio 2.02, 95% CI 1.2 to 3.5, p = 0.01). Conclusions: Researchers designing and conducting phase 2 trials should pre-specify and report criteria for concluding that the findings are ‘positive’. Researchers designing and conducting P3 trials of targeted and immunological therapies should require evidence of activity for the specific type(s) of tumour and therapy in question. [Table: see text]
Role of radiomics to differentiate benign from malignant pheochromocytomas and paragangliomas on contrast enhanced CT scans.
Authors: Laderian Bahar , Ahmed Firas Salem , Zhao Binsheng , Wilkerson Julia , Dercle Laurent , Yang Hao , Guo Xiaotao , Pacak Karel , Lee James A. , Bates Susan Elaine , Del Rivero Jaydira , Schwartz Lawrence Howard , Fojo Antonio Tito 
Published: May 2019

e14596 Background: Radiomics features, which are quantitative features generated by computational analysis of routine clinical imaging like CT scans, have been shown to be associated with clinical outcomes and tumor’s behavior in some solid tumors. We compared the radiomic features of malignant and benign pheochromocytomas/paragangliomas (P/P). Methods: Through an IRB approved study at our institution, we identified 20 consecutive patients with P/P and with available contrast-enhanced abdominopelvic CT. A radiologist with experience in oncologic imaging identified and segmented tumors on every slice using a MatLab-based imaging platform. The entire tumor image then underwent computational analysis generating 1160 radiomics features reflecting tumor size, shape, density, textural heterogeneity, and margins. These radiomics features were compared between malignant and benign P/P using Wilcoxon-Rank sum test. Results: Of the twenty patients included in this analysis, there were 6 patients with malignant P/P and 14 patients with benign tumors. Patients had been followed for at least 5 and many for at least 10 years after resection of the tumor. At diagnosis, the mean age of patients with benign and malignant tumors were 51 and 45, respectively. A 60% majority of patients with benign tumors were females while a 77% majority of patients with malignant tumors were male. Benign P/P were significantly different from malignant ones in: tumor intensity textures (spatial correlation [p-value = 0.0010], Laws [p-value = 0.0064], LoG [p-value = 0.0087], and Gabor [p-value = 0.0325]), and tumor local surface shape (Shape Index SI7 [p-value = 0.0325]). Conclusions: This initial analysis sought to discern differences in these rare tumors that might be exploited clinically. The results show that compared to benign tumors, malignant P/P tend to have more heterogenous texture, irregular edges, and less rounded shape on contrast enhanced abdominal CT scan. However, because these radiomics phenotype properties are subtle, they cannot be made reliably in an objective fashion using human visual assessment and thus these radiomics features may have a role as a quantitative imaging biomarker in P/P to predict tumor behavior. The cohort is being expanded and data will be updated at the time of the presentation. With larger numbers, the contribution to the radiomics profile of a SDHx mutation will be explored in greater depth to understand the differential impact of SDHx loss and of evolution into a cancer to the radiomics profiles.
Quantitative image profiling of the tumor microenvironment on double stained immunohistochemistry images using deep learning.
Authors: Nagy Mate Levente , Juncker-Jensen Anna , Ovadia Ben , Smale Robert , Yamamoto Karen , William Josette , Hoe Nicholas , Padmanabhan Raghav 
Published: May 2019

e14619 Background: Spatial locations of immune cells in the tumor microenvironment (TME) correlate with clinical outcome in cancers. A worse patient outcome has been reported in oral squamous cancer for individuals with an increased number of regulatory T cells within 30µm of CD8+ cells [1]. The spatial relationship between CD8+ and PD-L1+ cells has become an area of interest for understanding PD-L1 inhibition. The combined assessment of CD8 and PD-L1 in NSCLC tumors was shown to outperform CD8 or PD-L1 alone as prognostic markers for predicting treatment with immune checkpoint inhibitors [2]. Methods: As reported in these cases, quantifying spatial relationships between two biomarkers is valuable in providing clinical insights. Spatial analytics of the TME requires accurate cell segmentation and classification. To that end, NeoGenomics has developed a deep learning pipeline to automatically segment and classify cells from whole slide double stained IHC images. Results: In this study, we performed IHC double staining and cell classification analysis on two sets of assays (CD8+ PD-L1+ and CD8+ FoxP3+) in NSCLC tumors by modifying our MultiOmyx analysis pipeline [3]. In addition to cell segmentation and classification image outputs, we also generate tables with cell morphological information, phenotype counts and densities, and biomarker intensities that can be used to define H-score-like measures. Advanced spatial analytics is performed to identify clustering patterns of various phenotypes. These analyses enable investigation of complex cell interactions in TMEs. Conclusions: NeoGenomics quantitative double stained IHC assay is compatible with any two biomarkers of interest even if they are expressed on the same cell as long as the sub-cellular localization of the markers is different (membrane CD8, nuclear FoxP3). The combination of double staining for CD8+ PD-L1+ or CD8+ FoxP3+ and quantifying spatial relationships between the two biomarkers is capable of providing the needed context to guide treatment decisions. References: Feng Z et al., JCI Insight. 2017 Jul 20:e93652 Steele KE et al., J Immunother Cancer 2018;6:20 Nagy ML et al., AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL
Noninvasive prediction of future macrovascular invasion occurrence in hepatocellular carcinoma based on quantitative imaging analysis: A multi-center study.
Authors: Wei JingWei , Tian Jie , Fu Sirui , Lu Ligong 
Published: May 2019

e14623 Background: To investigate whether preoperative imaging-based analysis could help to predict future macrovascular invasion (MaVI) occurrence in hepatocellular carcinoma (HCC). Methods: A cohort of 224 patients with HCC was enrolled from five independent medical centers (training cohort: n = 154; independent validation cohort: n = 70). Predictive clinical factors were primarily selected by uni- and multi-variable analysis. CT-based imaging analysis was performed based on extraction of 1217 radiomic features. Recursive feature elimination and random forest (RF) were chosen as the optimal radiomics modelling algorithms. A clinical-radiomics integrated model was constructed by RF modelling. Cox-regression analyses further selected risk independent factors. Risk stratification was explored by Kaplan-Meier analysis with log-rank test, regarding to MaVI occurrence time (MOT), progression free survival (PFS) and overall survival (OS). Results: The clinical-radiomics integrated model could successfully predict MaVI occurrence with areas under curve of 0.920 (training cohort, 95% confidence index [CI]: 0.875-0.965) and 0.853 (validation cohort, 95% CI: 0.737-0.970). The radiomics signature added significant improvement to the integrated model in both training and validation cohorts with p-value of 0.009 and 0.008, respectively. Radiomic features: N25_ori_gldzm_IN (hazard ratio [HR]: 0.44; p = 0.001) and N25_Coif1_ngldm_DE (HR: 0.60; p = 0.016) were selected as independent risk factors associated with MaVI occurrence time. The cox-regression model could stratified patients into high-risk and low-risk groups in MOT (p < 0.001), PFS (p = 0.003), and OS (p = 0.007). Conclusions: The noninvasive quantitative imaging analysis could enable preoperative prediction of future MaVI occurrence in HCC with prognosis implication.
The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients.
Authors: Wei Jia , Zhang JieJie , Wen Qiang , Zhu Xiaoyi , Li Dapeng , Liu Baorui , Hu Jinwei , Wang Weifeng , Yao Ming , Wang Kai 
Published: May 2019

e14624 Background: ARID1A (the AT-rich interaction domain 1A) is one of the most commonly mutated genes in cancer, mostly caused by frameshift variants. Here, we describe the mutational landscape of ARID1A in Chinese cancer patients and its correlation with tumor mutational burden (TMB). Methods: Formalin fixed paraffin embedded (FFPE) samples of 3,828 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB were also acquired by NGS algorithms. Results: A total of 340 (8.9%) patients were found to have ARID1A variants. The frequency of ARID1A mutations was 4% in lung adenocarcinoma (N = 74/1833), 8% in squamous cell lung carcinoma (N = 23/278), 12% in colorectal adenocarcinoma (N = 61/530), 11% in hepatocellular carcinoma (N = 52/484), 14% in pancreatic adenocarcinoma (N = 25/177), 15% in gallbladder adenocarcinoma (N = 14/94), 22% in intrahepatic cholangiocarcinoma (N = 47/213), 20% in gastric adenocarcinoma (N = 39/200) and 26% in endometrial adenocarcinoma (N = 5/19). ARID1A variants included truncation (78%), missense/indel (non-frameshift substitution/indel) (16%), splicing site (4%) and rearrangement (2%). Truncation was the most common, recurring in a few hot spots (R1276*, D1850Gfs*4, A339Lfs*24, P224Rfs*8 and Q372Afs*28/Sfs*19). In general, ARID1A mutations correlated with higher TMB (median 17.6 vs 7.4 muts/Mb, P < 0.001) in MSS tumors; especially in lung adenocarcinoma (17 vs 7.5 muts/Mb, P < 0.01), squamous cell lung carcinoma (16.8 vs 11.2 muts/Mb, P < 0.01). TP53 (60%), APC (34%) and KRAS (32%) were the most common co-occurred mutated gene in ARID1A (+) tumors. In more than 20% of ARID1A mutations, PI3K/mTOR pathway genes were altered, such as PIK3CA, PTEN, RNF43 and PIK3R1 genes. Conclusions: Since ARID1A mutations correlate with higher TMB, it could be a potential predictor of response to PD-1/PD-L1 immune checkpoint pathway inhibitors. As reported, ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Patients harboring ARID1A and PI3K/mTOR pathway mutations may provide useful information for drug discovery and biomarker exploration.
Exceptions to the rule: Novel retrospective analysis of a single-center institution of the PSMA PET/CT modality.
Authors: Durkal Vipal P. , Rettig Matthew 
Published: May 2019

e14625 Exceptions to the Rule: Using Pathology as a Gold Standard to Evaluate the Sensitivity of PSMA PET/CT Modality. Background: The experience with the novel Ga-68 PSMA PET/CT imaging and its limitations are described anecdotally in the literature. Cases of false-positive PSMA PET/CT of various benign and malignant etiologies are described in case reports. False-negative PSMA PET/CT results are significantly less well characterized. Our analysis is based on the UCLA Cancer Center experience with patients who underwent PSMA PET/CT and subsequent biopsy of target lesions. Methods: Of 44 evaluable patients, we found four patients with false negative results based on the 'Gold Standard' of pathologic biopsy. In this context, false negative is defined as PSMA PET/CT negative but proven to be PSMA-expressing adenocarcinoma of the prostate using biopsy of target lesions. Results: In our analysis, we found several stark patterns of these false-negative lesions. The vast majority were pulmonary in origin (75%). Their average size was subcentimeter (0.96 cm). The average Gleason Score at diagnosis was relatively high (8.25), while the initial PSA at diagnosis was relatively modest (4.3). A majority (75%) of these patients received radiation to the prostate. In terms of treatment: a majority were on Androgen-Deprivation Therapy (75%); Abiraterone (50%); had received prostatectomy (100%). The average age at diagnosis was 65. Conclusions: False-negative adenocarcinoma of the prostate that has been-biopsy proven to express PSMA has not been described in the literature. This is the first such instance that we can encountered. The implications of this finding are potentially far-reaching, since the lung remains the second most common site of metastasis in prostate cancer after the bone. The average sub-centimeter size of the target lesions that were biopsied suggests that the density of PSMA receptors may have a role in the detection on Ga-68 PSMA PET/CT and correlate with sensitivity.
RERG involvement in the RAS pathway and ER-dependent transcription in breast cancer.
Authors: Hsu Pei-Chen , Ho Jar-Yi , Yu Cheng-Ping 
Published: May 2019

e14638 Background: Breast cancer is the highest incidence malignancies in women worldwide. Luminal breast cancers are typically estrogen receptor–positive with better prognosis. However, the rapid disease progression and the high relapse rate of this subtype of breast cancer have become a puzzle in breast cancer treatment. It gave us the motivation to figure out the anomalous molecular mechanism which devoted in. It has been well-documented that the RAS pathway is overloadly activated in more than half of human breast tumors. RAS genes encode a superfamily of small GTPases that contribute to cell growth signals. Methods: Gene expression level were measured by qPCR and Western Blot.Biological effects of each condition were evaluated in cell viability and migration. Results: In this study, we investigated one member of the RAS family, RERG, which was related to the ER pathway and contributed to inhibit Ras activated pathway. Our results showed that knockdown of RERG concomitantly promoted two major oncogenic pathways, Ras and Stat3 signaling pathways, in luminal type breast cancer cell lines. Moreover, ectopic RERG expression significantly inhibited Ras expression. It implicated that RERG mediated in RAS-driven biological effects. Our findings indicated that knockdown of RERG enhanced mobility of the breast cancer cells and made cells more intractable under SERM treatment. Conclusions: We elucidated the tumor-suppressor role of RERG in breast cancer cells though inhibition of the Ras and Stat3 signaling pathways. Therefore, this study might shed light on the important mechanistic insight into the tumorigenesis of ER-positive luminal type cancer and provided the prognostic and therapeutic improved roles of RERG.