bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic contrast-enhanced MRI versus 18F-misonidazol-PET/CT to predict pathologic response in bevacizumab-based neoadjuvant therapy in breast cancer.
Authors: Garcia-Foncillas Jesus , Martinez Purificación , Lahuerta Ainhara , Llombart Cussac Antonio , Garcia Gonzalez Maria , Gomez Rosa Maria Sanchez , Alvarez Isabel , Anton Antonio , Illarramendi Jose J. , De Juan Ana , Calvo Elena Galve , Plazaola Arrate , Morales Serafin , Hernando Blanca , Lao Juan , Boni Valentina , Puertolas Teresa , Sherer Stefan , Palacios Gemma , Lopez-Vega Jose Manuel 
Published: March 2020

10512 Background: To investigate the role of DCE-MRI versus 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) in the prediction of pathological response to bevacizumab-based neodajuvant therapy. Methods: 73 chemotherapy naïve, stage II and III breast cancer (BC) patients (pts) were enrolled in a phase II, single-arm, multicenter, open-label and prospective clinical trial. Pts received single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to the beginning of neoadjuvant chemotherapy (NAC) consisting of 4 cycles of docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/ kg) every 21 days (C2-C5), followed by surgery. Tumor proliferation, hypoxia and perfusion were evaluated respectively using 18F-Fluorothymidine (FLT) and 18F-Misonidazole (FMISO) positron emission tomography (PET/CT) and dynamic contrast enhancement magnetic resonance (DCE-MR). Serial imaging studies were performed in parallel at several time points including baseline (BL) and 14-21 days after bevacizumab alone (C1). Results: After only one administration of bev, tumor proliferation and perfusion assessed using FLT-PET and DCE-MRI significantly decrease (-26% and -46%, p<0.001) but these changes were not found to be associated with final response. Most important, changes in tumor hypoxia induced by bevacizumab was significantly associated with pathological response (p= 0.004) and was an independent predictor of response in multivariate analysis (RR=0.95, IC 95% 0.92-0.99, p=0.02). Decrease in FMISO uptake >10% yielded a ROC curve area of 0.7 (95% CI: 0.56 - 0.85) with high specificity (94%). Conclusions: Our findings suggest a significant value of early changes in tumor hypoxia assessed by FMISO-PET as a biomarker of pathological response in bevacizumab-based neoadjuvant therapy in breast cancer.
Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.
Authors: Chen Xiaoxia , Ren Shengxiang , Kuang Peng , Su ChunXia , Li Jiayu , Li Xuefei , Hu Qiong , Zhou Caicun 
Published: March 2020

10527 Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10-3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10-3 and 4.95±2.33×10-3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10-3 VS 2.69±3.97×10-3, P=0.006) or ALK positive (1.21±0.78×10-3VS 2.69±3.97×10-3, P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.
New microRNA-based diagnostic test for lung cancer classification.
Authors: Aharonov Ranit , Lithwick Yanai Gila , Benjamin Hila , Sanden Mats Olot , Bibbo Marluce , Thurm Craig , Horowitz Laurie , Huang Yajue , Feinmesser Meora , Barshack Iris , Hou Steve j , Edmonston Tina B , Ashkenazi Karin ,   Rosetta Genomics Inc.
Published: March 2020

10528 Background: Lung cancer is the leading cause of cancer deaths in the US. Treatment options are determined by tumor subtyping, for which there is lack of standardized, objective, and highly accurate techniques. In 20%-30% of cases significant limitations of tumor quantity and quality prevent full classification of the tumor using traditional diagnostic methods. Using microRNA microarray data generated from over a hundred formalin-fixed, paraffin-embedded (FFPE) primary lung cancer samples, we have identified microRNA expression profiles that differ significantly for the main lung cancer types. Based on these findings, we have developed and validated a microRNA-based qRT-PCR assay that differentiates primary lung cancers into four types: squamous cell carcinoma, non-squamous non-small cell lung cancer, carcinoid and small cell carcinoma. Methods: Over 700 primary tumor samples from different histological types of lung cancer were collected. Samples included FFPE blocks from resection or biopsies and cell blocks from cytology specimens including fine needle aspiration, bronchial brushing and bronchial washing. High-quality RNA was extracted from the samples using proprietary protocols. Expression levels of potential microRNA biomarkers were profiled using microarrays followed by a sensitive and specific qRT-PCR platform. An assay for lung tumors classification using 8 microRNAs on qRT-PCR was developed based on data from 261 samples. This assay was validated on an independent blinded set of 451 cytological and pathological samples. Results: Using the expression levels of 8 microRNAs measured in qRT-PCR, accurate classification of the primary lung tumors into the four main cancer types is obtained. The microRNA-based assay reached an accuracy of 94%. Moreover, cytological samples composed over 50% of the validation set and reached an accuracy of 95%. Conclusions: We present here a new microRNA-based assay for the classification of the four main types of lung cancer based only on the expression of 8 microRNAs. This assay displays very high levels of accuracy for both pathological and cytological samples. The assay comprises a standardized, well-tested and objective tool which can assist physicians in the diagnosis of lung cancer.
Promoter methylation of MGMT in paired primary and recurrent glioblastomas.
Authors: Bie Li , Qiu Ji Qing , McClelland Michael , Ju Yan 
Published: March 2020

10543 Background: Epigenetic sliencing of MGMT gene promoter in primary glioblastomas (GBM) of pts subsequently treated with temozolomide (TMZ) is associated with prolonged survival. Further, several studies have observed a change in MGMT silencing in paired primary and recurrent GBM. However, the relationship between this “MGMT switch” and patients outcome is largely unknown. Methods: The study involved primary and recurrent tumor tissue samples from 53 GBM pts diagnosed and treated within the First Hospital of Jilin University from Jan 2003 to Nov 2010. After surgical treatment, all pts were subjected to radiotherapy with concomitant administration of TMZ (75 mg/m2/d), followed by 5 cycles of adjuvant TMZ given at 4-weeks intervals. Pts that experienced recurrent tumors received TMZ at a dose of 200 mg/m2/5 days for 4 weeks. 53 pts underwent 58 further operations after recurrence (5 pts received a third surgery). MGMT promoter methylation levels were determined using qMSP. The relationship between “MGMT switch” and clinical outcome was investigated. Results: Fifty three (M/F=33/20; median age: 49.2±3.6, range: 19.5-72.3 ys) underwent a first operation for GBM. qMSP analysis revealed MGMT promoter methylation in 19 pts (35.8%, group A, OS 31.5 ms); no methylation in 34 pts (64.2%, group B, OS 7.9 ms). In the recurrent tumors, MGMT promoter methylation was detected in 25 pts (47.2%); and no methylation in 28 pts (52.8%). Comparison of individual pairs of primary and recurrent GBMs revealed a changed methylation status in 10 (18.9%), including eight changed from unmethylated to methylated tumors (15.1%, group C, OS 29.4 ms), two changed from methylated to unmethylated tumors (3.8%, group D, OS 10.5 ms). Median overall survival was 12.1 ms. MGMT promoter methylation was significantly associated with a favorable clinical outcome (group A vs group B, p=0.0027). The outcome of pts were not significant different between A and C (p>0.01). Conclusions: The methylation status of the MGMT promoter was altered in 10 (18.9%) of 53 recurrent GBM after chemoradiotherapy. Eight pts changed from unmethylated to methylated who have a median overall survival similar to methylated pts. The pts changed from methylated to unmethylated who have poor outcome.
Correlation between miRNA (miR) and gene expression profiles (GEP) and response to neoadjuvant chemotherapy (NT) in patients with locally advanced and inflammatory breast cancer (BC).
Authors: Li Sierra Mi , Wu Xiwei , Frankel Paul Henry , Gao Harry , Sun Guihua , De Snoo Femke , Rossi John , Wang Emily , Roepman Paul , Yen Yun , Peeters Justine , Stork Lisette , Somlo George 
Published: March 2020

10545 Background: GEP may predict for pathologic complete response (pCR). Correlation between miRs, GEP, and pCR may reveal novel targets. Methods: Patients (pts) with HER2- BC were randomized to receive docetaxel, doxorubicin, cyclophosphamide (TAC, arm A) or A and C given every 2 weeks x 4, followed by carboplatin and nab-paclitaxel (arm B). Pts with HER2+ BC received NT per arm B, with trastuzumab added (arm C). Core biopsies were snap-frozen prior to NT, and RNA extracted for gene array analysis (Agilent 44K microarray) and deep sequence miRNA analysis (Solexa/Illumina platform). HER2 testing by IHC [3+] or FISH and/or gene array was carried out (Blueprint). MiRs were measured in 72 of 119 enrolled pts. Of 882 miRNAs reported by Solexa sequencing, 487 were assessed (observed at raw counts > 10 in at least 3 pts). TargetScan was used to obtain miRNA targets and negative correlation between miR and mRNA expression was applied. Results: In 44 HER2- cases, we found 17 miRs differentially expressed between pts who achieved pCR vs. pts who did not (< pCR), 13 with predicted targets by TargetScan (TS). We found 28 canonical pathways (including Embryonic Cell, EGF signaling, Estrogen-dependent signaling) affected by the identified miRs, and inclusive of 74 target mRNAs identified (Agilent) and correlating with pCR. The top overexpressed miRs are 31 [gene targets: FZD4]; 18a [IGF1, ALDH5A1]; 19a [PIK3R, IGF1]) and 3 lowest expressors are miR-190b [MMP1]; 29c [FOS, WNT5B]; 342-3p [BMP7]. Among the 28 HER2+ cases there were 14 miRNAs differentially expressed between BCs with pCR vs <pCR, and 8 had predicted targets from TS. We found 10 canonical pathways (including p53, HER-2, PTEN) affected by miRs, which included 44 target mRNAs (Agilent) correlating with pCR. The most overexpressed miRs are miR-708 [gene target: RRM2B; 193a-p5 [BMPR1B, RPRM] ; 92b [CCNE2, DKK2]. The lowest expressors are: miR-30a [FZD1, SMAD1, TP63]; miR-450-5p [FOXO1, WINT5A, ERBB2]; miR-497 [PIK3R1, FGFR1, FOXO1]. Conclusions: Combined assessment of miRNA and gene expression patterns is feasible, and may yield information leading to individualized and improved NT.
Topoisomerase II alpha gene status, HER2, and microtubule-associated protein tau as predictors of pathologic complete response after neoadjuvant chemotherapy.
Authors: Barnadas Agust , Tibau Martorell Ariadna , Lopez Vilaro Laura , Escuin Daniel , Alonso M Carmen , Ojeda Belen , Ramon y Cajal Teresa , Fuentes M Josefa , Perez Garcia Jose Ignacio , Garcia Valdecasas Barbara , Clotet Montserrat , Torrubia M Sofia , Gich Ignasi , Lerma Enrique 
Published: March 2020

10555 Background: There is growing evidence that topoisomerase II-alpha (TOPOIIα) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER2 has been described as a marker of both anthracycline and taxane sensitivity.The goal of our study was to examine the predictive and prognostic value of TOPOIIα, MAPT and HER2 expression in breast cancer patients (pts) who received neoadjuvant chemotherapy (NAC) based on anthracycline-taxane regimens. We analyzed the relationship between these biomarkers and pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Methods: Between November 1993-2009, 140 pts (mean age 52 years) with locally advanced breast cancer (T1-4, N0-3, M0) were retrospectively studied. The study contained 2 groups: group A included 85 pts who received NAC with an anthracycline-taxane regimen and group B included the last 55 pts who received NAC with only an anthracycline-based regimen. HER2 was tested by immunohistochemistry (IH) or FISH, TOPOIIα by CISH and MAPT by IH. Expression of these proteins was evaluated in core needle breast biopsy. Results: Overall, 12 pts (8.5%) had a pCR. TOPOIIα was amplified in 6 (4%) of the tumors. Among pts without amplification, 6 (4%) had deletion of the TOPOIIα, and 10 (7%) polysomia of chromosome 17. TOPOIIα gene aberrations (amplification, deletion, polysomia), which was present in 22 (25%) of the tumors, was a strong predictive factor for pCR (p=0.018) but showed no direct association with prognostic outcome in multivariate analysis. HER2 amplification, which was present in 16% (21) of the tumors, show no direct association with pCR, DFS or OS. Finally, differences by treatment arm or pCR in low versus high MAPT expression groups were not observed, indicating that MAPT is not a useful predictive marker for taxane-based chemotherapy. In multivariate analysis high MAPT expression was associated with longer DFS (p=0.002). Conclusions: TOPOIIα gene aberrations but not HER2 are highly predictive of pCR for anthracycline-based regimen. MAPT is not associated with response to taxanes but has a prognostic value.
Exosomal-miRNA profiles as diagnostic biomarkers in cervical cancer.
Authors: Nishi Hirotaka , Nagamitsu Yuzo , Sasaki Toru , Takaesu Yotaro , Terauchi Fumitoshi , Isaka Keiichi 
Published: March 2020

10557 Background: MicroRNA (miRNA) expression is altered in cancer cells and associated with the development and progression of various types of cancer. miRNA could serve as diagnostic or prognostic biomarker for cancer patients. Our study was designed to analyze circulating exosomal-miRNA in patients with cervical cancer. Methods: Total RNA was extracted from serum in healthy women and patients with cervical intraepithelial neoplasia (CIN) and cervical cancer. We first explored miRNA expression profiles using miRCURY LNA microRNA Array (Exiqon) in each six malignant and healthy serum samples. miRNAs with significant differences in expression were validated in larger sample sets by a quantitative real-time RT-PCR using TaqMan gene expression assays (Applied Biosystems). Results: Six of 1223 miRNAs compared in serum samples from cervical cancer and normal control were found to have a >3.0-fold change with a P value <0.01 using miRCURY LNA microRNA Array. In a validation set (n=101), expression of 3 of the 6 miRNAs, miR-483-5p, miR-1246 and miR-1275, was significantly different between the cervical cancer (n=40) and control (n=20) samples. We also found that the median levels of these miRNAs were significantly higher in patients with cervical cancer (n=40) than those in CIN (n=41). Circulating miRNAs were not correlated with clinical-pathological parameters except for miR-1246. Compared to patients with squamous cell carcinoma, the miR-1246 level was significantly higher in those with adenocarcinoma. Whereas, receiver-operator characteristic (ROC) curve analyses suggest that these serum miRNAs may be useful markers for discriminating patients with cervical cancer from healthy controls. Conclusions: Expression of circulating miR-483-5p, miR-1246 and miR-1275 is significantly higher in the blood of cervical cancer patients compared to controls and may potentially serve as a useful biomarker for cervical cancer diagnosis. Especially, miR-1246 may be a candidate for early detection of cervical adenocarcinoma. Larger-scaled studies are warranted to fully explore the role of circulating exosomal-miRNAs in cervical cancer.
Evaluation of gene expression by RNA-seq after single dose of trastuzumab (T) reveals predictors of pathologic complete response (pCR) in HER2-positive early breast cancer.
Authors: Galanina Natalie , Sprecher Emmet , Bossuyt Veerle , Sarkar Sudipa , Krop Ian E. , Winer Eric , Tuck David P. , Bruce Can , Harris Lyndsay 
Published: March 2020

10558 Background: The use of a ‘brief exposure’ to single agent T allows the measurement of dynamic changes in the transcriptome that may predict response to T-based combinations. We have shown that most gene expression changes in HER2+ tumors treated with T occur in tumors that ultimately achieve a pCR. Our further analysis suggests several patterns of transcriptional change in pCR tumors suggesting different mechanisms of action of T. RNA-seq analysis provides more in-depth annotation of these mechanisms. Methods: Fresh tumor core biopsies were taken at a 2 week time point after a single dose of T (8mg/m2) from 80 HER2+ early breast cancer patients enrolled on a clinical trial of T>T+C. Nucleic acids were extracted using Qiagen AllPrep and were analyzed with Illumina HT12v3 Beadchip and Illumina 610 QUAD V1 SNP arrays. RNA was also processed for sequencing using the Ovation RNA-Seq System and paired-end sequenced using an Illumina Genome Analyzer IIxRNA-seq data was analyzed with Tophat/Cufflinks. Network analysis was performed with Metacore. Results: Among pCR tumors, distinct patterns of differential expression pre/post T were observed, in both microarray and RNA-seq data. ERBB2 down-regulation was characteristic of pCR in one subgroup by microarray. In this group, differentially expressed genes belonged to interaction networks involved in apoptosis and cell cycle regulation. In contrast, tumors with no change in ErbB2 showed differentially expressed genes that belonged to networks related to chromatin assembly and regulation of immune pathways. NOLC1, RPL41, ZCHHC17, and B2M had altered alternative splicing product distributions in both groups. In the ERBB2 down-regulated group, genes with changed expression were enriched for targets of STAT3 and YY1. Conclusions: RNA-seq and microarray reveal distinct responses in tumors that achieve pCR to T-containing regimens. These methods provide predictive markers for validation in subsequent clinical trials.
EGFR exon 20 insertion mutations: Incidence and clinicopathologic characteristics in U.S. patients with lung adenocarcinoma.
Authors: Arcila Maria E. , Nafa Khedoudja , Chaft Jamie E. , Rekhtman Natasha , Zakowski Maureen Frances , Kris Mark G. , Ladanyi Marc 
Published: March 2020

10560 Background: Activating insertion mutations in exon 20 of EGFR are reported in a small subset of lung adenocarcinomas (ADC). In contrast to the classic EGFR mutations, they appear to confer primary resistance to currently approved EGFR tyrosine kinase inhibitors. Their incidence and clinicopathologic features are not well established. Methods: Lung ADCs (n=1500) were screened for major activating mutations in EGFR (exons 19 and 21) and KRAS (exon 2). Negative cases were tested for EGFR exon 20 insertions by a PCR-based sizing assay. Extended testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed in all cases by Sequenom mass spectrometry. A subset of cases was also tested for ALK rearrangements by FISH. Results: We identified 32cases withEGFRexon 20 insertions, accounting for 11% of all EGFR mutations. EGFRexon 20 insertions were mutually exclusive with the other genetic alterations tested except for PIK3CA mutations. The incidence was higher among never-smokers (p<0.0001) but there was no association with sex, ethnic origin or stage at diagnosis. Insertions were 3, 6, 9 or 12bp; 9bp insertions were most common (50%, 16/32). Morphologically, 90% of tumors were moderate to poorly differentiated with a predominant mixed ADC phenotype. Conclusions: EGFR exon 20 testing may identify a unique subset of EGFR mutant lung ADCs which is significantly larger than previously reported, making this the third most common type of EGFR mutation after exon 19 deletions and L858R. This population could potentially benefit from alternate targeted therapies, many of which are currently in clinical development.
Correlation of the maximum standardized uptake value for f-18 fluorodeoxyglucose with molecular subtype and survival in advanced breast cancer.
Authors: Jia Zhen , Hu Xi-Chun , Zhang Yingjian , Zhou Min , Wang Biyun , Wang Zhong Hua , Zhang Yongping 
Published: March 2020

10567 Background: Tumor glucose metabolism correlates with tumor biology and clinical outcome of breast cancer patients. This prospective cohort study was to explore correlations of 18F-FDG uptake, a surrogate for glucose metabolism, with molecular subtypes in women with advanced breast cancer. Methods: Patients diagnosed as advanced breast cancer were enrolled in the study. PET/CT was performed and the Maximum Standardized Uptake Value (SUVmax) of each lesion was documented as baseline, so was clinical and treatment information. Diagnosis of malignant nature of a lesion was confirmed by pathology or further follow-up. Patients who had got a progressive disease in the efficacy assessment were assigned new treatments as per-institutional guidelines. Results: 244 patients met the criteria and were all put into this analysis. Independent factors for influencing SUVmax value included luminal subtype (p= 0.002), triple-negative subtype (p<0.001), ER status (p= 0.028), Her-2 status (p<0.001), and CEA level (p<0.001). A higher SUVmax was significantly associated with poorer median PFS (6.9 vs. 8.1 months, p=0.040) and OS (13.8 vs. 16.9 months, p=0.003). Cox Regression analysis showed that SUVmax value, previous treatments, subsequent treatments and treatment efficacy were four independent prognostic factors for PFS, while age, menopausal status, disease free interval, 4 subtypes, previous treatments, number of metastatic sites, SUVmax value and subsequent treatment efficacy were independent prognostic factors for OS. Conclusions: 18F-FDG uptake correlates with molecular subtypes in women with advanced breast cancer. Baseline SUVmax is an independent prognostic factor for survival of patients with advanced breast cancer, especially those with luminal subtypes.