bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgical treatment for intra-abdominal/retroperitoneal soft tissue sarcoma: A single center experience in Japan.
Authors: Yashima Jun , Shirai HIroyuki , Tojimbara Tamotsu , Ono Yasuo , Teraoka Satoshi 
Published: September 2018

e22539 Background: Surgical resection is considered the standard treatment for intra-abdominal and retroperitoneal soft tissue sarcoma(IARS) .We here report the outcome of surgical resection for IARS at IUHW Atami hospital, Japan. Methods: A total of 93 patients underwent 165 surgical resections for IARS between 2010 and 2016. Deta on primary and recurrent tumor were collected including staging, histopathological diagnosis, operative procedures, postoperative complications, and perioperative mortality, as well as 5-years survival. Results: The cohort consisted of 14(15.1%) primary and 79(84.9%) recurrent cases. 61(65.6%) were female and 32(34.4%) were male.The age ranged from 17 to 76 years (median 55 years).　Histopathologically, 13 different types of IARS were found in the cohort. Leiomyosarcoma(n = 46, 49.5%) and liposarcoma(n = 23, 24.7%) were the most common. 77patients(82.8%) had far-advanced stage disease(StageIIIA,IIIB,IV, by AJCC cancer stageing manual) The 5-years overall survival rate for all the patients was 56.7%. The 3-years survival rate from the surgery in our center for the recurrent cases was 40.7%. Patients with stageIII or IV disease, the-3years survival rate was 27.3% from the surgery in our center. Conclusions: Surgical resection may contributed to better survival even in the recurrent or far-advanced stage patients. It seems necessary for the better outcome to incorporate with other treatment modalities, such as chemotherapy or radiotherapy or ablation for liver metastasis.
Modulation of the anti-tumor activity of VEGF blockade by metformin.
Authors: Selmy Mohamed , Zulato Elisabetta , Pasto Anna , Indraccolo Stefano 
Published: September 2018

e23009 Background: The payoff from first-generation angiogenesis inhibitors was commonly temporary, due to the development of intrinsic as well as acquired resistance. Apart from the vascular resistance due to circumventing VEGF blockade by proangiogenic factors, resistance has also been associated with assortment of resistant clones. Accordingly, a combination strategy was proposed to overcome such resistance. Metformin, as a potential candidate, has received considerable concern as an anticancer agent. Methods: IN-VITRO WORK;Cells were divided into normoxic and hypoxic groups. For both, four subgroups were developed; control, metformin, glucose deprivation and a subgroup in which cells were subjected to both glucose deprivation and metformin treatment. Cells were then subjected to analysis for Apoptosis, Cell cycle progression and western blot. IN-VIVO WORK; Tumor growth was assessed IGROV-1 subcutaneous xenografts. Animal were divided into four groups; control, Metformin, Bevacizumab and a fourth group receiving both drugs. Tumor growth was assessed along treatments and at time of sacrifice.After sacrificing animals, tumors were further analyzed for; necrosis, apoptosis, proliferative capacity, activation of AMPK and its downstream effectors. Results: Our in-vitro results suggested an anti-proliferative effect of metformin in terms of apoptosis, cell cycle arrest, AMPK activation and mTOR inhibition at various time points. In-vivo experiments revealed a significant decrease of tumor weight and proliferative capacity in tumors treated with both drugs and a trend toward a decrease in tumor growth along the treatment. Yet, there was no difference between the bevacizumab and the combination groups regarding AMPK activation suggesting another mechanism to exert the combination effect. The effect of Metformin on CSC percentage and viability was tested. Glucose deprivation plus hypoxia lead to increase in CSC population, while adding metformin to bevacizumab reverse this augmentation in CSC numbers. Conclusions: Study represents a proof of concept study demonstrating a positive modulatory effect of metformin addition to bevacizumab. Additional experimental work on a wider scale is running to ascertain the current results.
Effect of very low doses of chemotherapeutic drugs on proangiogenic factors in tumor cells.
Authors: Ocal Muge , Sonugur Fatma Gizem , Babahan Cansu , Abdi Abgarmi Samira , Icli Fikri , Akbulut Hakan 
Published: September 2018

e23013 Background: The efficacy of the metronomic use of conventional chemotherapeutic drugs in the clinic has been linked to their anti-angiogenic activity. However, the dose level for the metronomic use of the drugs with regard to anti-angiogenic activity is not known. In the current study, we aimed to study the effects of very low doses of 5-florouracil (5-FU), irinotecan and oxaliplatin on the synthesis of pro-angiogenic factors in tumor cells. Methods: We first determined the IC50 doses of 5-FU, irinotecan, and oxaliplatin in human tumor cell lines (HT-29: colon cancer cells, MCF-7: breast cancer cells and LNCaP: prostatic carcinoma cells). Then we applied the drugs to the assigned cells at the dose levels of IC50, -1log, -2log and -3log of IC50. The effects of the drugs on both gene expression and protein secretion levels of pro-angiogenic genes including vascular endothelial growth factor A (VEGF-A), basic-fibroblast growth factor (bFGF), matrix metalloproteinase-9 (MMP-9), platelet-derived growth factor-beta (PDGF-B), interleukin-8 (IL-8) and factor secretion by real-time PCR and sandwich ELISA. Results: The IC50 levels of 5-FU, irinotecan, and oxaliplatin in tumor cells were found as shown in the Table. We found that -1logIC50 dose level of 5-FU efficiently suppressed the pro-angiogenic genes both at the gene expression and protein secretion levels. However, the -2logIC50 and -3logIC50 dose levels of both irinotecan and oxaliplatin significantly inhibited gene expression and protein secretion. Conclusions: In conclusion, our results suggest that irinotecan and oxaliplatin could be used as anti-angiogenic agents at the very low doses. The -1logIC50 dose for 5-FU and the -2log and -3logIC50 doses of irinotecan and oxaliplatin could be further tested in animal models and clinical trials. Table. The IC50 dose levels of the drugs in tumor cell lines. [Table: see text]
Association of circulating tumor cells (CTCs) with hyperglycemia in the follow-up of Chinese non-metastatic breast cancer patients.
Authors: Shi Yu-Mei , Zhang Guochun , Ren Chong-Yang , Wen Ling-Zhu , Zhu Wen-zhen , Chen Xiao-qing , Liao Ning 
Published: September 2018

e23020 Background: CTCs has been confirmed to associate with a poor outcome of breast cancer at primary diagnosis. To date, CTC has not been studied with sufficient details in the follow-up of non-MBC pts, especially in Chinese population. We investigated the associations of CTC with clinicopathological features and metabolic factors to gain insight into potential interactions between physiology and disease burden. Methods: We recruited 264 cases of postoperative pts with non-MBC in Guangdong General Hospital from Jan 2009 to Dec 2015. For each enrolled pts 7.5mL blood samples were drawn for CTC enumeration using the CellSearch system. CTC results were correlated with clinicopathological features, obesity related indicators and HBsAg. A multivariate logistic regression analysis was performed to further determine the independent predictors of CTC. The study defined CTC positive as CTC ≥1. Results: In 10.6 % of all pts (n = 28) a median of 1 (range, 1–108) CTC was detected. A pT1 tumor was present in 47% of pts, 11.4 % had G1 grading and 64.4 % were node-negative. The positive rate of CTCs in pts with IDC and ILC was lower than that in pts with other pathological types (9% and 11.1% vs 28.6% P=0.02). A similar trend that approached significance was noted for age (p=0.062), histological grade( p=0.087), invasion of the nipple areola (p=0.06). CTCs was positively correlated with blood glucose (p=0.015), and negatively correlated with high density lipoprotein (p=0.049). In addition, glycated hemoglobin was positively associated with CTC in correlations that neared significance (p=0.059). The result of multivariate logistic regression analysis is shown in the Table. No associations were observed in triglycerides, free fatty acid, total cholesterol, low-density lipoprotein and HBsAg. Conclusions: This study suggested pathological type and blood glucose were independent predictors of CTC, supporting the notion that high fasting glucose level in BC pts may have severe disease burden, leading to a higher frequency of CTC. [Table: see text]
LC-hrms metabolomics profiling in breast cancer: Searching for biomarkers in human plasma samples.
Authors: Sánchez Rovira Pedro , Ortega Granados Ana Laura , Fernández Navarro Mónica , Ruiz Sanjuan María , de la Torre Cabrera Capilla , García Verdejo Francisco José , Luque Caro Natalia , Fernández Garay David , Ramirez Tortosa Cesar , Collado Martín Ricardo , Pamplona Gras Reinald , Jové Font Mariona , Olid JA , Rivas V , Genilloud Olga , Díaz Navarro Caridad , Vicente Pérez Francisca , Lomas Garrido Maria , Jaén Morago Ana , Pérez del Palacio Jose 
Published: September 2018

e23053 Background: Breast cancer (BC) is most common cancer in women and development of new technologies for understanding molecular changes involved in BC progression is essential. Metabolic changes precede phenotypic changes, due to cellular regulation affects use of small-molecule substrates for cell division, growth or environmental changes, such as hypoxia. Metabolomics (profiling of metabolites in biofluid, cell and tissue) is routinely applied as a tool for biomarker discovery. Liquid chromatography−mass spectrometry(LC−MS)is the dominating platform. Methods: With the aim to find metabolomic profiles for diagnostic and prognostic of newly diagnosticated breast cancer (BC) we have investigated plasma samples in neoadjuvant setting (134 BC patients with median age of 51 years, stages T1-4,N1-2,M0 and 135 healthy controls) using high resolution mass spectrometry couple to liquid chromatography in reverse phase and HILIC modes which provided resolved chromatography of highly polar as well as hydrophobic analytes, enabling the analysis of a wide range of chemicals, necessary for untargeted metabolomics. Chromatograms were processed with software (Markerview) to generate a table listing retention times with associated ion masses and intensities. To identify potential biomarkers, we used in combination 2 independent variable selection techniques: principal component analysis and Student t-test. Results: We observed a significant difference in metabolic profile between the 2 groups. 15 molecular features [oleamide, KDNalpha2-3Galbeta1-4Glcbeta-Cer(d18:1/22:0)] were found significantly down/up regulated in BC patients compared with healthy subjects, and they were selected as diagnostic biomarkers. Additionally, ROC curve analysis was used to assess their clinical usefulness, obtaining an AUC of 0.963 (95% CI 0.919-0.989) when using a multivariate model of 3 features. As an outcome, we showed that selected biomarkers are useful as diagnostic biomarkers. Conclusions: The present study demonstrates potential of metabolomics in identifying novel biomarkers for BC. Further studies may reveal the potential of metabolites as diagnostics biomarkers for BC and their role in pathogenesis.
Comprehensive detection of ctDNA variants at 0.1% allelic frequency using a broad targeted NGS panel for liquid biopsy research.
Authors: Chien Richard , Brinza Dumitru , Gu Jian , Dhingra Dalia , Banjara Kunal , Li Yanchun , Bagai Varun , Schageman Jeoffrey , Ballesteros-Villagrana Efren , Chaudhary Ruchi , Hanif Khalid , Au-Young Janice , Hyland Fiona , Bramlett Kelli 
Published: September 2018

e23065 Background: Advances in non-invasive tumor biomarker research have shown that tumor cells release fragments of DNA called circulating tumor DNA (ctDNA) into peripheral blood. Somatic mutations representing the tumors could be successfully detected from isolated ctDNA, providing new potential for tumor sample assessment in addition to traditional tissue biopsy methods. However, the low amount of ctDNA in the blood, which can be less than 1% allelic frequency, presents significant challenges for reliable variant detection with NGS assays. Improvement of sequencing accuracy at low allelic frequency is a critical factor in the implementation of NGS in ctDNA liquid biopsy research. Methods: We demonstrate the technical feasibility for a sample-to-variant NGS workflow that utilizes a broad multi-gene panel to survey a comprehensive list of variants relevant to multiple tumor types for liquid biopsy research. The method includes novel library preparation and analysis reporting for Ion Torrent™ sequencing platforms. 20ng of input cell-free DNA was subjected to the library generation protocol. Prepared libraries were templated on Ion Chef™ and sequenced on Ion S5™. Results: We successfully optimized an NGS workflow that enables the simultaneous examination of more than 360 driver and resistance hotspot mutations in a single-pool assay panel, achieving high sensitivity and specificity with limit of detection at 0.1% allelic frequency. The targeted regions span genes and variants relevant to multiple tumor types for comprehensive variant detection across high-value content reviewed by industry experts and researchers. Sequencing on the Ion S5™ delivered > 95% on-target reads and uniform amplification across targeted regions with deep sequencing depth ( > 40,000x). The workflow is compatible with single or multiple pooled samples on Ion Torrent™ sequencing chips. Conclusions: We demonstrate the ability to accurately detect high-value variants implicated in multiple tumors at 0.1% allelic frequency on Ion Torrent™ NGS. (For Research Use Only. Not for use in diagnostic procedures.)
Post resection circulating residual disease monitoring in early stage lung and colorectal cancer patients using a circulating cell-free DNA assay with ultra-high accuracy and specificity.
Authors: Maslan Annie , Jaimovich Ariel , Rajagopalan Narsi , Tan Michelle , Mortimer Stefanie , Chudova Darya , Kennedy Drew , Kim Hee Cheol , Kim Seung Tae , Lee Se-Hoon , Lee Jeeyun , Eltoukhy Helmy , Kim Jhingook , Talasaz AmirAli 
Published: September 2018

e23068 Background: Analysis of cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is a promising method for detecting and monitoring earlier stage cancers. Liquid biopsies have a large potential to detect cancer earlier upon initial recurrence and to aid in adjuvant decision making through a non-invasive and highly accurate mechanism. Methods: We developed a 30kb ctDNA capture panel based on the landscape of genomic alterations in ctDNA of over 10,000 advanced cancer patients with high theoretical clinical sensitivity for colorectal (96%) and lung (87-93%) cancers. The panel was validated with high analytical PPV (86% at MAFs < 0.025%, 96% at MAFs > 0.025%). We applied the panel to a clinical study of 63 healthy donors and also 40 early stage (II/III) CRC and lung cancer patients with both pre- and post-tumor resection blood draws. Tumor samples were also collected at the time of the surgical resection. Results: Overall, the detection rate of ctDNA in pre-op blood draws was 72% (13/18) in CRC and 67% (12/18) in lung cancer patients. In the post-op blood draws ctDNA was detectable in 11% (2/18) of CRC and 11% (2/18) of lung cancer cases. For lung cancer patients, the median MAF in pre-op was 0.06% (0.01%-8.47%, n = 51) and in post-op was 0.06% (0.02%-4.14%, n = 38). For CRC patients, the median MAF in pre-op was 0.18% (0.01%-9.26%, n = 51) and in post-op was 0.36% (0.04%-9.5%, n = 18). Sixty-three healthy donor plasma samples were screened at similar cfDNA input amounts and nine (14%) had mutations; the majority of the mutations were also detected in matched leukocyte DNA. To assess a clinically relevant biological false positive background rate in lung cancer patients, screening of cancer-free smokers is ongoing. Conclusions: We have developed a highly sensitive and specific universal assay for the detection of ctDNA in early stage CRC and lung cancer patients without the requirement of a priori knowledge of tumor mutations. This technology allows for a promising non-invasive route for molecular monitoring of residual disease post-surgery and for early detection of relapse compared to traditional methodologies.
Pembrolizumab in gastrointestinal (GI) malignancies with defective DNA mismatch repair (dMMR): A single institution experience.
Authors: Cavalieri Courtney Christine 
Published: September 2018

e23081 Background: Defective DNA mismatch repair is associated with increased mutation load and expression of neoantigens. Increased activity of PD-1 inhibitor is reported in patients with GI cancers with dMMR. Here, we describe our experience at Huntsman Cancer Institute with PD-1 inhibition in subjects with GI malignancies with dMMR. Methods: Retrospective chart review of patients with metastatic GI malignancies with dMMR, treated with pembrolizumab at Huntsman Cancer Institute between July 15, 2015 and February 6, 2017. Results: A total of 9 patients were identified that received at least 1 dose of pembrolizumab [colorectal (CRC) n = 4; extrahepatic cholangiocarcinoma (EHCC) n = 2; pancreatic adenocarcinoma (PDAC) n = 2; adenocarcinoma of the appendix n = 1]. Five patients received concurrent cytoxic chemotherapy at some point in treatment. Median number of doses given: 6.5 (3-18). Median age: 61 years (33-73 years). Eight patients were evaluable for response per RECIST. Two patients had complete responses (EHCC and CRC). Two patients had a partial response: PDAC (-57%, time to progression [TTP] +11 months) and CRC (-38%, TTP +6 months). Three patients had stable disease: PDAC (-28%, TTP +5 months), CRC (-6%), and adenocarcinoma of the appendix. One patient with CRC died from upper GI bleeding. Two patients experienced toxicities requiring discontinuation of pembrolizumab. The first patient experienced grade 3 hyperthyroidism and adrenal insufficiency. The second patient had an incidental finding of pneumonitis and enlarged mediastinal lymph nodes on restaging CT scan, biopsy showed non-necrotizing granulomas consistent with sarcoidosis. One patient had grade 2 pneumonitis that was treated and resolved on steroids. This patient continues on pembrolizumab. Conclusions: Single-institution data seem to confirm activity of PD-1 inhibitor in GI malignancies that harbor dMMR. At time of abstract submission, six patients remain on single agent pembrolizumab. Complete responses were seen in CRC and EHCC. Two patients (PDAC and CRC) attained a partial response. Updated responses for all patients will be presented during the meeting.
Research on the diversity of T cell receptor repertoire in the process of malignant transformation of HBV chronic infection.
Authors: Zhang Henghui , Chen Yanhui , Li Guoli , Zeng Hui , Chen Hongsong 
Published: September 2018

e23086 Background: The progression of liver inflammation resulted from HBV infection is the main cause of HBV-related liver cancer. T cells play a central role in anti-HBV and anti-tumor specific immune response during disease progression, and the T cell receptor (TCR) repertoire can quantitatively reflect the immune function of T cells. The accurate information of TCR repertoire change in the progression from chronic hepatitis B to tumor was obtained in this study. Methods: CD4+ T cells from the spleens of mice and CD8+ T cells from 50ml peripheral blood of the patients with chronic hepatitis B and liver cancer were sorted by flow cytometry for establishing next generation sequencing (NGS) and the related bioinformatics research system of TCR repertoire. The sequence in V region of TCR was amplified bu using 5 'RACE technology with the mRNA as template. The sequences of TCRα and TCRβ were determined by the NGS technology, and the sequence data with 6Gb were obtained for each chain of each individual. Results: Acoording to analysis of TCR repertoire in mouse CD4+ T cells, the V-J pairing and diversity of CDR3 sequence in TCRβ were higher than TCRα; With the increasing of the recombination number in D gene fragments in the TCRβ chain, a higher diversity of V-J pairing could be introduced in TCRβ.Acoording to analysis of TCR repertoire in human CD8+ T cells, the effects of chronic hepatitis and HCC condition on the overall diversity of TCR receptor repertoire were not significant; The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers; the distinctive V-J paring and CDR3 could be detected in the group of patients with chronic hepatitis and HCC based on the above TCR clone at the level of low frequency. Conclusions: NGS sequencing and the related bioinformatics research system of mouse and human TCR repertoire were established. The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers.
Regulation of PD-L1 in breast cancer.
Authors: Zerdes Ioannis , Tsesmetzis Nikolaos , Lovrot John , Rolny Charlotte , Bergh Jonas C. S. , Rassidakis Georgios , Foukakis Theodoros 
Published: September 2018

e23088 Background: Programmed death ligand 1 (PD-L1, CD274) is currently being investigated as a therapeutic target in breast cancer (BC), however its transcriptional regulation has not been elucidated. Methods: Three BC cells lines, one negative (MCF7) and two positive (MDA-MB-231, BT549) for PD-L1 were used. Protein expression of potential regulators of PD-L1, including Myc, STAT3, p-rpS6 (mTOR effector), Erk and p53 was assessed by western blotting and immunohistochemistry. Furthermore, transfections with small interfering RNAs (siRNAs) of selected proteins or plasmids and pharmacologic inhibition were performed. Fluorescent in situ hybridization (FISH) analysis was used for PD-L1 gene amplification studies. Publically available gene expression data derived from The Cancer Genome Atlas (TCGA) database (cBioportal) were analyzed for correlations between mRNA levels of PD-L1 and potential regulators. Results: PD-L1 gene amplification was not detected in BC cells expressing PD-L1, suggesting non-genetic regulation of PD-L1 expression. Additionally, the correlation between CD274 transcript levels and copy-number alterations (CNA) in primary BC was weak. Pharmacological treatment with either Myc (expressed in MDA-MB-231) or mTOR (p-rpS6 expressed in all three cell lines) inhibitors did not affect PD-L1 expression. STAT3 protein was expressed in all cell lines and STAT3 mRNA levels had a weak positive correlation with PD-L1 (Spearman’s rho = 0.25) in the TCGA dataset. Both gene silencing using STAT3 siRNA and pharmacologic inhibition of STAT3 activity resulted in decreased PD-L1 protein levels in BT549 and MDA-MB-231 cells respectively. Multiple DNA binding sites for STAT3 were identified in silico on the PD-L1 gene promoter suggesting that the observed regulatory effects are likely transcriptional. Conclusions: STAT3 can act as an inducer of PD-L1 expression, while Myc and mTOR seem to have no effect in PD-L1 regulation in BC.