bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic impact of PD-1, PD-L1, and CD8 genes expression in peripheral blood in gastric cancer.
Authors: Ito Shuhei , Masuda Takaaki , Fukagawa Takeo , Kouyama Yuta , Wakiyama Hiroaki , Yoshikawa Yukihiro , Noda Miwa , Kidogami Shinya , Hu Qingjiang , Sato Kuniaki , Nambara Sho , Saito Tomoko , Sakimura Shotaro , Hayashi Naoki , Kuroda Yousuke , Eguchi Hidetoshi , Sasako Mitsuru , Mimori Koshi 
Published: September 2018

11531 Background: Programmed death 1 (PD-1)/PD-1 ligand (PD-L1) blocking agents to gastric cancer (GC) in the clinical setting show significant therapeutic promise. However, since these agents are enormously expensive and potentially toxic, it is crucial to identify predictive biomarkers for detecting the best candidate who would benefit from these agents by less invasive and simpler method, such as liquid biopsy. Methods: Expression levels of genes coding for PD-1, PD-L1 and CD8 (CD8+ T cells are closely associated with cellular immune responses to tumors) were assessed in peripheral blood (PB) samples using quantitative RT-PCR. Samples were obtained from 407 GC patients (392 patients with neoadjuvant chemotherapy [NAC] and 15 patients without NAC) before surgery and 23 PB from normal controls (NC). Flow cytometric analysis was performed to identify PD-1-expressed cells in PB mononuclear cells. Results: PD-1, PD-L1 and CD8 mRNA levels of GC patients were significantly higher than those of NC: 4.2-, 3.0- and 6.1-fold increases, respectively (P < 0.0001, P = 0.0001 and P < 0.0001). PD-1 mRNA levels were significantly lower in GC patients with NAC than in GC patients without NAC (P < 0.01). GC patients with low PD-1, high PD-L1 and low CD8 mRNA levels had significantly poorer overall survival (OS) than those with high PD-1, low PD-L1 and high CD8 mRNA levels, respectively (P < 0.05, P < 0.05 and P < 0.05). Multivariate analysis showed that PD-1 low/ PD-L1 high mRNA levels was independent risk factors for OS (OR 2.15, 95%CI 1.29-3.45, P < 0.01). Flow cytometric analysis demonstrated the proportion of CD3 (T cell marker)-positive cells in the PD-1-positive fraction were 95.4 ± 6.9% in GC patients. Thus, most PD-1 protein expression occurred on T cells. Taken together, PD-1, PD-L1 and CD8 mRNAs in PB were overexpressed in GC patients, and PD-1 mRNA levels which was mostly expressed on T cells in protein levels in PB were decreased in GC patients with NAC. Furthermore, relative levels of PD-1, PD-L1 and CD8 were associated with prognosis, respectively. Conclusions: Preoperative PD-1, PD-L1 and CD8 mRNA levels in PB may reflect antitumor immune response, and PD-1 low/ PD-L1 high mRNA levels in PB are markers of poor prognosis in GC patients.
Evaluation of liquid biopsies for molecular profiling in patients with advanced non-small cell lung cancer (NSCLC) in the relapse treatment setting.
Authors: Remon Jordi , Besse Benjamin , Lacroix Ludovic , Mezquita Laura , Jovelet Cecile , Howarth Karen , Plagnol Vincent , Morris Clive D. , Nicotra Claudio , Pannet Chloe , Green Emma , Soria Jean-Charles 
Published: September 2018

11532 Background: Molecular profiling is limited by access to sufficient tumor tissue for comprehensive analysis and due to tumor heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumor DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for the detection, quantification and monitoring of molecular abnormalities for personalized treatment strategies. Methods: In a prospectively designed program, to date, we have recruited 227 advanced NSCLC patients having received prior therapy, with unknown molecular profile at time of blood collection. Blood collections (10ml K2-EDTA) were performed to assess molecular profile prior to or at time of relapse. Repeat samples were performed on patients initiated on treatment and followed for up to 18months. Patient samples were analyzed with InVision (enhanced tagged-amplicon sequencing) using a 34 gene panel. Interim analysis performed with full descriptive summary statistical analyses to be presented at conference. Results: ctDNA profiling detected somatic mutations in 182pts (80.2%), predominantly located in TP53 (46%), EGFR (28%), KRAS (11%) and STK11 (7%, half of which had concurrent KRAS). Of note, clinically actionable mutations were detected: T790M (25pts, median 1.4% AF), ERBB2 (8 pts), MET (8pts) and BRAF (4pts) providing eligibility for new therapy options. 20pts including 12 EGFR/T790M+ve were evaluated for ctDNA monitoring up to 18 months (median 10m); correlation between dynamic change in mutation allele fraction and clinical response was observed, especially predictive of relapse to treatment. 10 patients demonstrated SD/PR response to osimertinib treatment with T790M detection at low allele fraction (7/10 < 1% AF with 1pt at 0.08% AF). Conclusions: ctDNA can be used as a non-invasive ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be repeated as needed where tissue is not feasible, providing real-time information to support personalised treatment.
CK19 combined with contrast-enhanced ultrasound: A prediction model for non-sentinel lymph node involvement in early breast cancer.
Authors: Yu Xingfei , Zhou Linyan , Liang Chenlu , Wang Chen , Li Yongfeng , Yu Yang , Chen Daobao , Yang Chen , Yang Hongjian , Huang Jian 
Published: September 2018

11539 Background: According to Z0011 and AMAROS trials, patients with breast cancer stage cT1~2cN0 and sentinel lymphnode (SLN) 1~2 involvement can avoid axillary lymphnode dissection (ALND). But the risk of non-sentinel lymphnode (nSLN) involvement in those early stage patients is still unclear and it is difficult to predicting the risk before surgery. Our previous study showed CK19 mRNA in peripheral blood had predicative value of nSLN involvement. Also, contrast-enhanced ultrasound (CEUS) is a new effective method exmaming axillary lymph node. We aim to establish a prediction model for nSLN involvement in early breast cancer using CK19 combined with CEUS score. Methods: We identified 119 cases diagnosed early breast cancer (stage cT1~2cN0 and 1~2 SLNs involvement as in Z0011 and AMAROS trials) from Oct 2015 to Nov 2016 in Zhejiang Cancer Hospital. The CK19 mRNA of peripheral blood by RT-PCR and CEUS score of axillary lymph nodes were acquired before surgery. We used logistic regression analysis for filtering out valuable predictive clinical parameters and establishing formulas to calculate the probability of nSLN involvement. Our model was compared with Memorial Sloan Kettering Cancer Center (MSKCC) nomogram, which is one of the most reliable and validated methods for predicting of nSLN. Results: The histological grade, CK19 and CEUS score were screened by logistic regression analysis into the formula to calculate the probability of nSLN involvement. The sensitivity, specificity, total accuracy of this model was 89.13%, 80.82% and 84.03%, respectively. The false negative rate was 10.87%. The model had high quality of consistency (Kappa 0.675, p < 0.01) and goodness of fit (likelihood-ratio test, -2log liklihood = 84.607). The area under curve (AUC) of ROC was significantly higher (P < 0.01) in our model (0.914, 95%CI, 0.863~0.965) than in MSKCC nomogram (0.563, 95%CI, 0.459~0.667). Conclusions: The prediction model based on CK19 and CEUS score has satisfying sensitivity, specificity and accuracy, more effective than MSKCC nomogram. It is a valuable model of evaluating the risk of nSLN involvement in early breast cancer before surgery, picking out the patients who can truly avoid ALND.
Early TKI-pharmokinetics and circulating tumor DNA (ctDNA) to predict outcome in patients with EGFR-mutated non-small cell lung cancer (NSCLC).
Authors: Bigot Frederic , Pecuchet Nicolas , Blanchet Benoit , Laurent-Puig Pierre , Blons Helene , Goldwasser Francois , Boudou-Rouquette Pascaline , Auclin Edouard , Oudard Stephane , Fabre Elizabeth 
Published: September 2018

11544 Background: Erlotinib (E) and gefitinib (G) are indicated as first-line therapy of EGFR-mutated NSCLC patients (pts). Many studies highlighted TKI pharmacokinetic (PK) impact on toxicities. However, data about the relationship between PK and efficacy are sparse. Recently, ctDNA has been shown to be a strong prognostic factor for metastatic NSCLC pts undergoing specific treatment. Thus, we underwent an observational study to determine plasma drug concentration and ctDNA impact on outcomes in NSCLC pts treated with E or G. Then, we explored the correlation between PK and ctDNA in order to improve management of pts treated with EGFR-TKI. Methods: We analyzed consecutive pts with EGFR-mutated NSCLC treated with TKI in Cochin and European Georges Pompidou hospitals (APHP, Paris) from April 2010 to March 2016. Plasma samples were collected 2 to 6 weeks after TKI initiation. Steady state trough concentration (Cssmin) was assessed by high performance chromatography. CtDNA was analyzed using Next-Generation Sequencing (Ampliseq ColonLungV2 panel, BPER method). Therapeutic ranges obtained from previous studies were between 1200 to 2000 ng/mL and > 200 ng/mL for E and G, respectively. Results: Out of 77 pts, 56 had Cssmin analysis, 40 ctDNA analysis and 31 both. Median age was 70 years (range: 31-90), 49 were treated with E, 24 with G. Median follow-up was 19 months. Whatever EGFR TKI, pts with Cssmin into therapeutic ranges had longer PFS than pts over or under-exposed (median: 17.5 vs 7.5 months, p = 0.002). Those with early indetectable ctDNA had significantly better PFS (median 13 vs 5.8 months, p = 0.01) and OS (median: 21.4 vs 14.3 months, p = 0.02). No correlation was found between ctDNA and Cssmin. Occurrence of toxicity > grade 2 in pts treated with E was associated with higher plasma concentration (mean 1991 vs 1184 ng/mL, p < 0.01). Conclusions: Early Cssmin and ctDNA assessment appear as markers to predict outcomes. Our observational study is the proof of concept that pts undergoing EGFR-TKI therapy could be monitored with Cssmin and ctDNA to define optimal personalized treatment strategies. A prospective study is planned to evaluate dose adaptation of TKI based on those 2 tools.
Exosomal Del-1 as a potent diagnostic marker for breast cancer: A prospective cohort study.
Authors: Lee Soo Jung , Lee Jeeyeon , Jung Jin Hyang , Park Ho Yong , Lee Chan-Hyeong , Moon Pyong-Gon , Baek Moon-Chang , Jeong Jae-Hwan , Park Ji-young , Chae Yee Soo 
Published: September 2018

11548 Background: The authors recently reported exosomal Del-1 as a diagnostic marker for breast cancer (Moon PG et al, Clin Cancer Res. 2016). Therefore, the current study aimed to confirm the diagnostic role of exosomal Del-1 in a prospective cohort with breast cancer by comparing plasma exosomal Del-1 levels before and after curative surgery. Methods: To identify the optimal time of sampling after surgery, blood samples were serially collected at day 1, 3, 5, and 7 after surgery from 22 patients with breast cancer. Thereafter, one hundred fourteen breast cancer patients who underwent curative surgery were prospectively enrolled and then their exosomal Del-1 levels before and after surgery were compared using ELISA with both anti-Del-1 and anti-CD63 antibodies. Results: Among 22 patients for identifying the optimal sampling time, all the exosomal Del-1 levels were normalized at post-operative day (POD) 1 (0.5 or less), and therefore POD 3 or later was accepted for the sampling time for 114 prospective patient cohort.At diagnosis, exosomal Del-1 levels of 110 (96.5%) patients were higher ( > 0.5) and 109 (99.1%) patients showed a normalization of Del-1 after surgery including four patients with the borderline Del-1 (between 0.4 and 0.5). During the mean follow-up duration of 21.8 (range, 5.9 – 58.4) months, nine (7.9%) patients experienced relapses (4 loco-regional and 5 distant), where 3 out of 6 in high group ( > 0.5), 2 out of 4 in borderline group, and 4 out of 105 in normalized group (≤0.4). In particular, patients who relapsed in higher Del-1 group showed earlier relapse compared to the relapsed patients in lower Del-1 group. Conclusions: As the current prospective cohort study demonstrated a normalization of exosomal Del-1 after curative surgery, exosomal Del-1 can be confirmed as a potent diagnostic biomarker for breast cancer. Plus, a high Del-1 level after surgery seems related with early relapse suggesting a potential prognostic marker by identifying the existence of residual tumor.
Prognostic value of NK and T-lymphocytes markers in operable non-small cell lung cancer (NSCLC).
Authors: Skrzypski Marcin Tomasz , Szymanowska-Narloch Amelia , Jassem Ewa , Marczyk Michał , Polanska Joanna , Biernat Wojciech , Rzyman Witold , Maciejewska Agnieszka , Pawlowski Ryszard , Jassem Jacek 
Published: September 2018

11556 Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p < 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. < 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.
Adjuvant radiation therapy to induce a transitory adaptive up-regulation of programmed death ligand 1 (PD-L1) on circulating epithelial tumor cells (CETCs) to affect the anti-tumor immune response in primary breast cancer patients.
Authors: Schott Dorothea , Pizon Monika , Pachmann Katharina , Pachmann Ulrich A. , Maeurer Matthias 
Published: September 2018

11558 Background: Radiation therapy (RT) is an integral part of the treatment of breast carcinoma but unfortunately many patients experience local recurrence. During the inflammatory response that accompanies radiation tumor cells may develop multiple resistance mechanisms for example the up-regulation of PD-L1 on tumor cells which leads to immune evasion. Since CETCs arise from the tumor it is conceivable that under evolutionary pressure they might share some of the immune escape mechanism inherent to tumor cells. In this study we demonstrate that RT leads to a transitory adaptive up-regulation of PD-L1 expression on CETCs. Methods: CETCs and the expression of PD-L1 and Ki-67 were analyzed from 25 patients with primary non-metastatic breast cancer using the maintrac method. The fraction of PD-L1 and Ki-67 positive CETCs were assessed at baseline, 3 and 6 weeks after start of RT and 6 weeks after end of therapy. Additionally, copy number status of PD-L1 was determined using FISH. Results: Fractionated-dose RT leads to a significant increase in PD-L1 expression on CETCs with the highest expression level midterm of irradiation as compared to baseline (49% vs. 74%, p < 0.01). 6 weeks after end of RT the number of PD-L1 positive CETCs returned to baseline value. The up-regulation of PD-L1 was dose dependent. Patients who received higher total dose had significantly more PD-L1 positive CETCs as compared to patients treated with lower total dose midterm of RT (64% vs. 43, p < 0.05). Before start of therapy there was a correlation between the fraction of PD-L1 and Ki-67 positive CETCs (r = 0.6, p < 0.01). PD-L1 copy number gains were significantly associated with PD-L1 expression (r = 0.6, P < 0.05). Conclusions: RTleads to an up-regulation of PD-L1 expression on CETCs, which could be a possible mechanism of acquired radioresistance. Combining immunomodulatory agents with radiation might have the potential to overcome this resistance and could improve clinical outcome in breast cancer.
Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels to predict efficacy of bevacizumab in metastatic colorectal cancer patients receiving first-line chemotherapy.
Authors: Suenaga Mitsukuni , Cao Shu , Zhang Wu , Ning Yan , Okazaki Satoshi , Berger Martin D. , Miyamoto Yuji , Schirripa Marta , Gopez Roel , Melendez Elizabeth , Soni Shivani , Barzi Afsaneh , Yamaguchi Toshiharu , Lenz Heinz-Josef 
Published: September 2018

11564 Background: Early VEGF-A reduction by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BV). CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in CCL5/CCR5 pathway will predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) receiving BV in first-line setting. Methods: Genomic DNA was extracted from 215 samples of three independent cohorts: 61 pts receiving FOLFOX+BV (median age 60 yrs, median follow-up 39.2 mos); 83 pts receiving FOLFOX (median age 61 yrs, median follow-up 57.6 mos); 71 pts receiving FOLFOX/XELOX+BV as exploratory for serum biochemistry assay (median age 60 yrs, median follow-up 28.9 mos). Single nucleotide polymorphisms of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Serum VEGF-A levels at baseline and day 14 were measured using ELISA. Results: In univariate analysis for the FOLFOX cohort, pts with the CCL5 rs2280789 G/G variant or any CCR5 rs1799988 T allele had shorter overall survival (OS) compared to the those with any A allele or the C/C variant (18.7 vs. 29.4 mos, HR 1.93, 95%CI: 1.05−3.53 P= 0.025; 22.0 vs. 31.2 mos, HR 1.74, 95%CI: 0.98-3.90, P= 0.055). The trend remained in multivariable analysis ( P= 0.090 and P= 0.026). The differences were not confirmed in the FOLFOX+BV cohort. Pts with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and OS when receiving FOLFOX+BV than FOLFOX (PFS: 19.8 vs. 11.0 mos, HR: 0.44, 95%CI: 0.25-0.78, P= 0.002; OS: 41.8 vs. 21.1 mos, HR: 0.43, 95%CI: 0.24-0.77, P= 0.002); pts carrying any CCR5 rs1799988 T allele had longer PFS and OS ( P= 0.025 and P= 0.008, respectively). No significant difference was shown in pts with either A/A or C/C variant. In the exploratory cohort, any CCL5 rs2280789 G allele was associated with higher VEGF-A levels at baseline and greater decrease of VEGF-A levels at day 14 compared with the A/A variant. Conclusions: CCL5 and CCR5 impact the angiogenic environment. Our data suggest the genotypes may identify specific populations who benefit from BV-based chemotherapy in first-line treatment for mCRC.
Computer extracted measurements of vessel tortuosity on baseline CT scans to predict response to nivolumab immunotherapy for non-small cell lung cancer.
Authors: Khunger Monica , Alilou Mehdi , Thawani Rajat , Madabhushi Anant , Velcheti Vamsidhar 
Published: September 2018

11566 Background: Immune-checkpoint blockade treatments, particularly drugs targeting the programmed death-1 (PD-1) receptor, demonstrate promising clinical efficacy in patients with non-small cell lung cancer (NSCLC). We sought to evaluate whether computer extracted measurements of tortuosity of vessels in lung nodules on baseline CT scans in NSCLC patients(pts) treated with a PD-1 inhibitor, nivolumab could distinguish responders and non-responders. Methods: A total of 61 NSCLC pts who underwent treatment with nivolumab were included in this study. Pts who did not receive nivolumab after 2 cycles due to lack of response or progression per RECIST were classified as ‘non-responders’, patients who had radiological response per RECIST or had clinical benefit (defined as stable disease >10 cycles) were classified as ‘responders’. A total of 35 quantitative tortuosity features of the vessels associated with lung nodule were investigated. In the training cohort (N=33), the features were ranked in their ability to identify responders to nivolumab using a support vector machine (SVM) classifier. The three most informative features were then used for training the SVM, which was then validated on a cohort of N=28 pts. Results: The maximum curvature ( f1), standard deviation of the torsion ( f2) and mean curvature ( f3) were identified as the most discriminating features. The area under Receiver operating characteristic (ROC) curve (AUC) of the SVM was 0.84 for the training and 0.72 for the validation cohort. Conclusions: Vessel tortuosity features were able to distinguish responders from non-responders for patients with NSCLC treated with nivolumab. Large scale multi-site validation will need to be done to establish vessel tortuosity as a predictive biomarker for immunotherapy. [Table: see text]