bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of lymphocyte-neutrophil relationship in patients with advanced kidney cancer and the response to one-line treatment with target therapies.
Authors: Acosta Luciana Paola , Richardet Martin Eduardo , Molina Matias , Richardet Eduardo 
Published: September 2018

e23034 Background: In kidney cancer, some important prognostic factors of survival are known and inflammation plays a key role. It has been proven that cancer progress is not only determined by the characteristics of the tumor but also by the response of the host. It is known that a high RNL has been identified as an independent prognostic factor associated to poor survival in several/different types of cancer, including breast cancer, colon cancer, gastric cancer, mesothelioma and pancreas. The primary aim was to evaluate if RNL can be used as a prognostic indicator of SLP in patients with advanced CCR with 1st line treatment with tirosin-kinasa inhibitors. The secondary aim was to evaluate whether there was a relationship between prognostic factors, smoking habits, BMI, anemia, calcemia, KPS and nephrectomized patients as opposed to those who were not operated with RNL and SLP. Methods: Retrospective and analytical study. The medical histories from patients with metastatic kidney cancer diagnosis were analyzed as well as those who were undergoing treatment with Sunitinib and Pazopanib. The cut value of > ó < 3 was taken as a reference point for RNL. Overall survival analysis will be evaluated through the Kaplan-Meier curve and the meaning will be verified by the log-rank test. The multivariate analysis will be done through the Chi-square test. Results: A total of 65 patients were included in this study. 50 patients (75.38%) received treatment with Sunitinib and 15 patients (24.62%) with Pazopanib. It was observed that RNL < 3 was correlated with a higher SLP 21,6 months vs 8.9 months, p = 0,00002 and it was statistically significant. In subgroup analysis, those patients with normal values of corrected calcium the survival was 20 months vs 12, 2 months (p: 0.01), non-smokers 21 months vs 12 months (p: 0.05), KPS > 1 17,72 months Vs 8,8 months (p: 0.03) and a RNL < 3 showed a higher survival in a statistically significant way. There were no differences in survival when we performed the anemia analysis, BMI, smoking habits and KPS 0 to 1. Conclusions: We can conclude that those patients with RNL < 3 and who had already undergone treatment with ITK revealed a better SLP in a statistically significant way.
Circulating tumor DNA profiling of lung cancer patients treated with EGFR inhibitors.
Authors: Ortiz-Cuaran Sandra , Swalduz Aurelie , Green Emma , Avrillon Virginie , Epstein Michael , Howarth Karen , Marteau Solène , Morris Clive D. , Perol Maurice , Saintigny Pierre 
Published: September 2018

e23060 Background: The presence of a targetable driver mutation in nearly 50% non-small cell lung cancer (NSCLC) patients has enabled tailoring therapy regimens to improve survival. Serial repeat biopsies can offer an instrumental indication into the longitudinal evolution of cancer. However, tissue biopsies are invasive and can provide insufficient material for molecular testing. Mutation detection in plasma DNA as a “liquid biopsy” has been suggested as non-invasive approach to monitor tumor dynamics over time. Methods: We established an institutional protocol (NCT01511288) for the collection of liquid biopsies from stage IIIB/IV NSCLC patients either untreated, under therapy or progressive on therapy with a TKI. This protocol has included 134 NSCLC patients for whom clinical, pathological and genomic information is collected prospectively. Analyses were performed by Inivata using InVision (enhanced tagged-amplicon sequencing). Results: So far, samples from 50 patients have been analyzed. InVision allowed the detection of driver mutations in 20 plasma samples obtained at diagnosis. Tissue was unavailable for molecular analysis in 8/20 samples. We observed a concordance rate in mached plasma and tissue samples, of 92,3% (n = 12). In plasma samples from patients that relapsed under erlotinib or gefitinib we evidenced the EGFR T790M mutation in 57% of patients, with a concordance rate of 90,9%. Interestingly, analysis of serial samples collected from 3 patients under EGFR-targeted therapy showed the emergence of an EGFR T790M mutation 11 weeks before the radiographic confirmation of progression (P1); differential dynamics in the allelic fractions of mutated clones that reflected the pattern of dissociated tumor response to treatment (P2) and the presence of concomitant EGFR activating and T790M mutations, together with an EGFR C797G, BRAF V600E and KRAS G12D in a patient who progressed under osimertinib (P3). Conclusions: Our preliminary results provide further evidence on the use of liquid biopsies for monitoring disease response, resistance to treatment and tumor heterogeneity. Subsequently, we will evaluate the utility of liquid biopsies in the clinical setting to understand the dynamics of mutant clones over time.
Serum thioredoxin reductase 1 as a diagnostic marker for non-small cell lung cancer.
Authors: Kang Xiaozheng , Dong Chaoran , Shen Bocun , Yin Hanwei , Xu Guobing , Chen Ke-Neng , Zeng Huihui 
Published: September 2018

e23069 Background: Non-invasive diagnostic markers for patients with suspicious non-small cell lung cancer (NSCLC) may provide needed guidance on invasive diagnostic and therapeutic decisions. Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme, and plays an important part in tumor growth, progression, metastasis, and chemotherapy resistance. The goal of this study is to test the feasibility of developing plasma TrxR1 as a novel diagnostic marker for NSCLC. Methods: The plasma TrxR1 activity was determined spectrophotometrically by monitoring the NADPH-dependent production of 2-nitro-5-thiobenzoate at 412nm and at 37℃. All detection kits and automatic analyzer possess independent intellectual property rights, and have been widely used in breast cancer screening. Results: In this study, the plasma levels of TrxR1 were measured in 109 treatment-naïve resectable NSCLC patients and 15 individuals with benign tumor-like pulmonary diseases. Taking plasma TrxR1 activity of 5.0 as reference, the overall concordance rate was 58.1%, while those of CEA, CA199, CA125, NSE, CYFRA21-1 and SCC were 19.2%, 8.2%, 2.1%, 45.9%, 25.3% and 9.5%, respectively. Furthermore, using TNM staging (AJCC 7th ed.) as classifier, the concordance rates of TrxR1 in benign tumor-like pulmonary diseases, local and regional stage NSCLC subgroups were 53.3% (8/15), 57.5% (46/80) and 63.0% (17/27), respectively. A multipoint linear fitting correlation model was created, and the equation was TrxR1 = 5.716 + 0.4898*Stage. Conclusions: Our data suggest that plasma TrxR1 activity is a useful non-invasive diagnostic marker for NSCLC, and there may be a linear correlation between TrxR1 activity and pathological stage.
Association of mesenchymal subtype with the presence of immune infiltrates in squamous cancer classifier.
Authors: Seitz Rob , Hout David Richard , Ring Brian Z , Bailey Dan B 
Published: September 2018

e23073 Background: Lehmann and colleagues (Lehmann 2011) devised a classification system for triple negative breast cancer (TNBC) consisting of seven subtypes—IM, BL1, BL2, LAR, M, MSL, and UNS. Recent work has shown the IM group (characterized by the presence of immunomodulatory genes) is due to tumor infiltrating lymphocytes (TILs), and should be measured independently of the other subtypes. Furthermore, the m subtype (characterized by genes associated with epithelial-mesenchymal transition (EMT)) was shown to have a highly inverse relationship with the IM group (Lehmann 2016). We (Ring 2016) modified the original algorithm into a 101-gene algorithm that also confirmed this inverse relationship between IM and m signatures (Grigoriadis SABCS 2016). While this is a novel and interesting finding, we wanted to know whether this inverse relationship applies to other epithelial cell origin cancers such as squamous lung cancer. Methods: We downloaded gene expression data from 548 squamous cell lung cancers from the TCGA database, and applied the 101-gene TNBC algorithm to the lung cohort without optimization or adjustment. Results: Of the 548 samples, 389 (71%) were able to be classified by the 101-gene algorithm. Of these, 82 (21%) had an m phenotype. 128 patients (33%) were positive for the IM signature. The expected overlap of patients positive for both IM and m was 27 patients (7%). The observed overlap was 0 patients (chi-squared = 29; p < 0.001). Conclusions: The unoptimized 101-gene TNBC algorithm validated the observation that gene expression signatures for IM and m are inversely correlated. While any attempt to apply a TNBC algorithm to squamous lung cancer would need careful optimization and validation, these data support that the inverse relationship noted in TNBC may transcend the tissue of origin.
Reduction of immune inhibitory myeloid derived suppressor cells by low dose sunitinib combined with a cancer vaccine to provide therapeutic benefit to tumor-bearing mice.
Authors: Cho Helen Kim , Cockle Paul , Li Cindy Wei , Burgess Steve , Coleman Terrence , Harder Terri , Xu Dan , Chan Kam , Kurzyniec Steve , Guo Joan , Maldonado Oscar , Merson James , Jooss Karin 
Published: September 2018

e23084 Background: Sunitinib is a receptor tyrosine kinase inhibitor (RTK) approved as a monotherapy for the treatment of advanced RCC, gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. At the approved doses, it inhibits angiogenesis in tumors and targets RTKs (PDGF receptor, VEGF receptor, KIT, FLT-3, and RET) involved in tumor cell growth. Sunitinib also has been shown in murine studies and patients, to exhibit immunomodulatory properties that reduce a heterogeneous population of cells termed myeloid derived suppressor cells (MDSCs) and restore the immune stimulatory Th1 cytokine profile of T cells. The approved anti-angiogenic sunitinib dosing regimens in RCC have a safety profile that is overall manageable with the most commonly reported sunitinib-related grade 3 adverse events including hypertension, fatigue, diarrhea and hand-foot syndrome. Although the tolerability of sunitinib as monotherapy was acceptable in advanced stage diseases, the drug’s side effect profile could potentially pose challenges for use in combination with other oncology therapies. Thus, if the dose of sunitinib could be lowered to improve the side effect profile without impacting its immune modulatory properties, it could be combined with cancer vaccine regimens, offering a better tolerated and highly potent immunotherapy for patients with cancer of all stages. Methods: To evaluate the relationship of dose of sunitinib on its immunomodulatory properties, the pharmacokinetic profile, the frequency of MDSCs, cytokine profile, vaccine induced immune responses and anti-tumor efficacy were monitored in a subcutaneous tumor bearing BALB-neuT mice in the presence or absence of a cancer vaccine. Results: The data suggested that sunitinib doses below the approved daily dose of 50 mg may maintain the drug’s immune modulatory properties and improve overall survival when given concurrently with a cancer vaccine. Conclusions: The data suggested that low dose sunitinib can be administered as an immunomodulator to reduce MDSCs safely in combination with potent, multi-component cancer vaccine regimens.
Spatial concordance of tumor proliferation and accelerated repopulation from pathologic images to 18F-FLT PET images.
Authors: Meng Xue , Zhang Xiaoli , Sun Xindong , Yu Jinming 
Published: September 2018

e23100 Background: PET imaging with 18F-fluorothymidine (18F-FLT) can potentially be used to identify tumor subvolumes for selecting dose escalation in radiation therapy. The aim of this study was to monitor tumor cell proliferation and repopulation during fractionated radiotherapy and investigated the spatial concordance of tumor cell proliferation and repopulation with 18F-FLT tracer uptake. Methods: Mice bearing A549 xenograft tumors were assigned to 5 different irradiated groups (3f/6d, 6f/12d, 9f/18d, 12f/24d and 18f/36d) with 2 Gy/fractions and non-irradiated group. Serial 18F-FLT micro PET scans were performed at different time points, the maximum of standard uptake value (SUVmax) were measured to detect the feasible time of tumor repopulation during irradiation. Ex vivo images of the spatial pattern of intratumor 18F-FLT uptake and Ki-67 labeling index (LI) were obtained from thin tumor tissue sections. A layer-by-layer comparison between SUVmax and Ki-67 LI results, including the thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation, were conducted to evaluate the spatial imaging pathology correlation. Results: The SUVmax were observed decreases in the 3f/6d group (P = 0.000), compared to these for non-irradiated tumors. However, it was significantly increased in the 6f/12d later, and then gradually reduced with treatment time prolonged again after 6f/12d group. Proliferation changes on pathology imaging at 6f/12d were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI of all ROIs in each in vitro tumor of cell proliferation group (Ps < 0.001). Similar results were also found in each tumor of accelerated repopulation group (Ps < 0.001). Furthermore, both of the mean ORRs were more than 50% in all layer of the tumor cell proliferation and accelerated groups. Regions of high-intensity 18F-FLT uptake in the autoradiographs exhibited prominent staining for Ki-67. Conclusions: 18F-FLT PET may be a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and might help make adaptive radiation oncology treatment plan.
Comprehensive genomic sequencing for triple negative breast cancer in Japan.
Authors: Nagahashi Masayuki , Hayashida Tetsu , Kitagawa Yuko , Futamura Manabu , Yoshida Kazuhiro , Kuwayama Takashi , Nakamura Seigo , Toshikawa Chie , Yamauchi Hideko , Kaneko Koji , Sato Nobuaki , Tsuchida Junko , Yuza Kizuki , Shimada Yoshifumi , Ichikawa Hiroshi , Ring Jennifer E. , Lyle Stephen , Okuda Shujiro , Takabe Kazuaki , Wakai Toshifumi ,   NGST-Japan
Published: September 2018

e23122 Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( > 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.
Evaluation of the correlations between patient-derived xenograft (PDX) model-based mouse trials and cancer patient-based clinical trials.
Authors: Gu Zhenyu , Jiang Jingjing , Yan Ying , Tan Tingting , Yu Tengfei , Liu Zhenhua , Du Wei , Yang Xuqin , Qiu Ling , Ye X. Katherine 
Published: September 2018

e23140 Background: Clinical trial to evaluate the safety and efficacy of an oncology drug candidate in general is a long and expensive process required for regulatory approval in drug development. High failure rates and difficulties to predict the outcome of clinical trials have wasted the resources and hindered the progress to bring more cancer drugs to patients. PDX models have been widely used recently in preclinical efficacy studies of new cancer agents. Comparing with tumor cell line derived xenografts, PDX models showed more similarities to cancer patients in tumor pathological features, molecular changes and drug responses. More importantly, the large number of available PDX models make it feasible to do preclinical tests in large scales which can represent cancer complexity similar to clinical trials with cancer patients. Methods: At GenenDesign, we have established over 1000 PDX tumor models in various cancer types and derived about 200 acquired drug resistance models. In our in house studies, we have tested near 40 treatments with standard of cares (SoCs) and late stage clinical drug candidates either as mono-therapies or combination therapies, and have generated over 3300 drug response datasets. Many tests with targeted drugs are based on cancer gene aberrations as predictive biomarkers. The drug responses were analyzed by Modifying Response Evaluation Criteria in Solid Tumors (mRECIST) method. Results: By comparing the mRECIST scores in mouse trials with results from about two dozens of historical clinical trials at phase 3 or phase 2, we found that there are high correlations in the rates of objective response (OR), stable disease (SD) and progressive disease (PD) between the mouse trials and their counterpart clinical trials. Progression-free survival also showed similar patterns in these analyses. Conclusions: PDX based mouse trials have advantages in flexibility of study design, quickness in testing new drug candidates and direct comparison of multiple drug treatments in the same models. It can provide valuable information on clinical trial outcome prediction and support clinical study design and patient selection.
Salinomycin reduces the viability of circulating epithelial tumor cells (CETCs) and tumorspheres cultured from circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with solid cancer.
Authors: Pizon Monika , Schott Dorothea , Pachmann Katharina , Pachamnn Ulrich , Szalus Norbert 
Published: September 2018

e23143 Background: Recently the hypothesis has been proposed that a more aggressive subpopulation of circulating tumor cells, circulating cancer stem cells are the source of metastatic spread from the primary tumor. These cells are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. The antibiotic Salinomycin has been shown to reduce the expression of markers for stemness and spheroid-forming ability. In this study, we evaluated the cytotoxic effect of salinomycin on CETCs and tumorspheres cultured from cCSC. Methods: 20 patients with solid tumors in different stages of disease were included. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. To evaluate the cytotoxic effect of salinomycin on CETCs and spheroids they were exposed to different concentrations of salinomycin in short time culture for different periods of time. Results: 80% of patients had detectable CETCs but sphere formation was observed in 95% of solid cancer patients. Growth of spheroids was detected also in patients without CETCs. The number of tumorspheres increased significantly with tumor progression. Treatment with salinomycin showed an 80% reduction in spheroid formation compared with control. Salinomycin reduced the viability of spheroids in a dose–dependent manner. Salinomycin had stronger cytotoxic effect on CETCs in non-metastatic as compared to metastatic patients (median of dead CETCs 85% vs. 34%, p < 0.001). Patients without chemotherapy responded better to salinomycin treatment than patients after several lines of chemotherapy (median of dead CETCs 87%vs.35%, p < 0.001) Conclusions: Using a method for cultivation of tumorspheres from blood of cancer patients and an effective in vitro platform for screening anti-cancer stem cells drugs was developed. Thus it could be shown that salinomycin targets not only more differentiated circulating cancer cells but also cancer stem cells from peripheral blood. It may evolve as a novel and promising therapeutic strategy for future cancer treatment
Concordance between comprehensive cancer genome profiling in plasma and matched tumor specimens.
Authors: Menon Roopika , Müller Judith N , Falk Markus , Lakis Sotirios , Mariotti Erika , Leenders Frauke , Bertrand Miriam , Neemann Nicole , Netchaeva Maria , Heukamp Lukas C. , Gloeckner Christian , Tiemann Markus , Heuckmann Johannes , Griesinger Frank 
Published: September 2018

e23146 Background: The importance and clinical use of liquid biopsies to identify somatic, targetable alterations in the plasma of cancer patients is steadily increasing. However, their concordance with alterations identified in cancer specimens tested in routine diagnostics is not being monitored. In a cohort of non-squamous cell lung cancer patients, our aim was to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 cancer related genes (NEOliquid) with alterations identified by routine diagnostics in a certified central pathology laboratory. Methods: Routine Diagnostics: DNA mutational analysis was performed using cobas or Sanger-Sequencing. Rearrangements were identified using immunohistochemistry or FISH. NEOliquid assay: Cell-free DNA from plasma was subjected to hybrid-capture based next-generation sequencing to detect point mutations, small insertions and deletions, copy number alterations and genomic translocations in 39 clinically relevant genes in a single assay. To evaluate and compare the performance of liquid biopsies, we applied the NEOliquid tests on blood samples of 82 non-squamous NSCLC patients and correlated them with results of routine diagnostics of matched tissue samples. Results: Routine diagnostics for lung cancer related oncogenes (EGFR, ALK, ROS1, KRAS, BRAF) identified a total of 50 somatic alterations of which 37 were point mutations, 11 InDels and 2 gene fusions. NEOliquid analysis of the corresponding plasma sample revealed a total of 34 alterations, including 21 targetable driver alterations. Overall, the concordance of mutation calls between routine diagnostic testing and NEOliquid was 97.6%, with a sensitivity of > 70% and a specificity of 100%. Importantly, NEOliquid identified additional clinically relevant genomic alterations, not covered by routine testing. Conclusions: We have shown high concordance of genomic alterations identified from liquid biopsies and tumor tissue specimens. The excellent specificity of actionable alterations identified by NEOliquid offers analytical performance for routine diagnostic use.