bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genomic profiling to merge precision medicine with immunotherapy.
Authors: Lyle Stephen , Tse Julie Y , Sun Ruobai , Huang Xiu , Russell Meaghan , Jiang Jane , Vuzman Dana , Protopopov Alexei , Eifert Cheryl 
Published: September 2018

e23108 Background: Immunotherapy is rapidly emerging as one of the most promising therapeutic options in clinical oncology. However, not all patients will respond to immune-oncology drugs and diagnostic assays are urgently needed to identify biomarkers that predict response to these therapies. We developed an assay that utilizes next generation sequencing data to simultaneously determine different types of somatic changes in tumors. The assay was designed, in part, to facilitate identification of cancer patients most likely to respond to immunotherapies by detecting 1) CD274 (PD-L1) copy number alterations, 2) viral infections (HPV16/18 and EBV), 3) microsatellite instability (MSI), and 4) tumor mutation burden. Methods: We developed a 435-gene panel assay (CancerPlex) with the goal of identifying all the genomic changes that inform treatment decisions with the highest possible accuracy. We thoroughly evaluated the performance of the assay using reference samples that represent all classes of genetic variation, including SNPs, indels, copy number changes, rearrangements, HPV/EBV infection and MSI. FFPE clinical samples were also evaluated to assess the ability of the assay to detect genetic variation in complex, heterogeneous tumors. Results: The assay has excellent performance, with a mean sensitivity of 99.4% and specificity of 99.9% for detecting somatic mutations with an allele fraction as low as 10%. The assay identified the MSI status of colorectal tumors with the same sensitivity as immunohistochemistry but with greater sensitivity than PCR. We also showed that calculating tumor mutation burden using the 435-gene panel predicts response to pembrolizumab as effectively as using whole exome sequencing. Among 892 patients across all tumor types, 6.8% were identified as candidates for immunotherapy based upon high tumor mutation burden and/or MSI status. Conclusions: The capacity of the 435-gene panel to determine all of the critical genetic changes, tumor mutation burden, MSI status, CD274 (PD-L1) CNVs, and HPV/EBV status has important ramifications for patient treatment strategies, including identification of patients who are more likely to benefit from immune checkpoint inhibitor therapies.
Comparison of the c-MET gene amplification between primary tumor and metastatic lymph nodes in non-small cell lung cancer.
Authors: Fang Mei-yu , Xu Chun-wei , Wang Wen-xian , Wu Mei-juan , Zhuang Wu , Lin Gen , Chen Xiao-hui , Zhu You-cai , Liao Xing-hui , Du Kai-qi , Huang Yun-jian , Xu Hai-peng , Chen Yan-ping , Chen Gang , Lv Tangfeng , Song Yong 
Published: September 2018

e23138 Background: Activation of c-MET lead to a wide range of biological activities. MET has recently been identified as a novel promising target in NSCLC, some c-MET inhibitors have been developed. The primary aim of this study was to evaluate the c-MET amplification status in advanced NSCLC and compare the consistency of c-MET amplification analyses in metastatic lymph nodes and tumor tissue.Methods: Real-time fluorescent quantitative polymerase chain reaction was used to test the tumor tissues in 368 patients of NSCLCs and 178 paired metastatic lymph nodes samples and compared the amplifications consistency inmetastatic lymph nodesand tissue samples, and analyzed the correlation between c-MET gene amplification and clinical characteristics of patients. Another 5 cases of normal lung tissue were taken as negative control.Results: The c-MET gene amplification rate was 8.97%(33/368) in tumor tissues . Of the178 paired cases, c-MET gene amplification was positive in 7.95%(15/178) cancerous tissuesand18.54%(33/178) in metastatic lymph nodes; Of these patients,13 were positive in the two kinds of samples. 20 cases in the paired group were detected positive c-MET in metastatic lymph nodes but was negative in cancerous tissues; 2 cases in the paired group were detected positive c-MET gene amplification in cancerous tissues but was negative in metastatic lymph nodes,there were statistically significant differences between the two samples (χ2= 45.536, P < 0.001). c-MET gene amplification was detected more in metastatic lymph nodes than the primary cancerous tissue. Consistency was evaluated by consistency test(Kappa = 0.482, P < 0.001).When lymph nodes were used as surrogate samples of primary cancerous tissues, sensitivity was86.67%, the specificity was 87.69%.Conclusions: More c-MET gene amplification positive were detected in metastatic lymph nodes compare with the primary cancerous tissue. c-MET gene amplification detected in lymph node metastases could screen more patients suitable for TKI therapy. Lymph node Metastasis can predict the c-MET gene amplification of primary tumor, and guide the clinical use of gene targeted drugs.
Activation of intracellular signaling pathways as a new type of biomarkers for selection of target anticancer drugs.
Authors: Buzdin Anton , Sorokin Maxim , Glusker Alexander , Garazha Andrew , Poddubskaya Elena , Shirokorad Valeriy , Naskhletashvili David , Kashintsev Kirill , Sokov Dmitry , Suntsova Maria , Roumiantsev Sergey , Kovalchuk Olga , Gaifullin Nurshat , Tkachev Victor , Borisov Nicolas 
Published: September 2018

e23142 Background: Anticancer target drugs (ATDs) specifically bind and inhibit molecular targets that play important roles in tumorigenesis. More than 150 different ATDs have been approved for clinical use worldwide, and the clinicians are faced with the problem of choosing the best therapeutic solution for each patient. The problem of efficient ATD selection remains largely unsolved and personalized approaches are needed to select the best ATD candidates for individual patients. Methods: We propose a new approach termed OncoFinder. It is based on digesting gene expression profiles for the analysis of activation of intracellular signalling pathways as a marker for the selection of target therapies. The original bioinformatic algorithms were integrated with the databases featuring molecular drug targets, compositions of signalling pathways, including the functional role of each gene product, for more than 1700 pathways (Buzdin, Front.Genet 2014; Ozerov, Nature Communications 2016). Results: We showed that pathway activation strengths are more stable and reliable biomarkers of cancer than the expressions of individual genes. OncoFinder allows to detect changes at the level of pathway activation and to predict the effectiveness of drugs based on the knowledge of their molecular targets. We applied it to find new biomarkers of clinical response to the ATD cetuximab; for modelling the combined chemotherapy of acute myeloid leukemia and combined anti-VEGF/BRAF therapy of melanoma. For two unrelated datasets obtained for colon cancer patients before treatment with the ATD bevacizumab, we were able to distinguish between those who responded to treatment and not (p < 0.01). We next assayed biopsies for kidney cancer patients with known responses to the ATD sorafenib. The responders and non-responders showed a significant difference (p = 0.02). Finally, the OncoFinder platform was prospectively used for decision making support to patients with advanced metastatic solid tumors (n = 23). The efficiency of the ATD treatment was 61% (complete + partial response, RECIST). Conclusions: OncoFinder method may be effective for predicting response to ATD based on high throughput gene expression profiles.
Regulation of the oxidative processes as a possible mechanism of iron nanoparticles antitumor action.
Authors: Kachesova Polina S. , Goroshinskaya Irina A. , Borodulin Vladimir B. , Nemashkalova Ludmila A. , Chudilova Anastasiya V. , Kit Oleg I. 
Published: September 2018

e23160 Background: It has been shown that metal nanoparticles (NPs) can inhibit a tumor growth. Oxidative processes play important roles in tumor development and growth. The aim of this study was to determine parameters of oxidative stress in the blood of tumor-bearing animals depending on the antitumor effect of iron NPs (30-50 nm). Methods: Male rats with transplantable lymphosarcoma (LS) in the main group (n = 21) were treated with eight i.p. injections of iron NPs (total doses of 10 mg/kg bw), the control LS rats (n = 20) received saline i.p. The activity of catalase, superoxide dismutase (SOD), content of glutathione (GSH) and malondialdehyde (MDA) in the red blood cells (RBC) and ceruloplasmin oxidase activity (CP) and MDA content in blood plasma were measured. These parameters were analyzed in rats with complete tumor regression (n = 12) after NPs treated and in cases of tumor growth (n = 9). Results: In RBC of control group the level of GSH and catalase activity were increased compared to healthy rats by 24% and 14.3% (p < 0.05), respectively. In spite of activation of the given antioxidant system components, the MDA content in RBC was increased by 45% (p < 0.01) compared to normal values. In plasma of control group we observed an increase in MDA by 167.4% (p < 0.01) and a decrease in CP by 36.8% (p < 0.001). In the main group there was a decrease in blood MDA level and the antioxidant system reorganization. The degree of changes depended on the antitumor effect of NPs: rats with tumor growth showed a tendency to the decreasing MDA in RBC and normalization of plasma MDA; MDA in rats with LS regression was similar to normal values. In the main group the CP activity did not differ from the values in healthy rats. GSH increased in animals with tumor growth by 218.6% and in the animals with the effect - by 69% compared to normal values (p < 0.01). SOD activity in the rats with LS growth increased by 42% and in the rats with LS regression it decreased by 30% (p < 0.01). Conclusions: The data suggest the relationship between antitumor effect and modulating action on oxidative processes in LS rats treated by iron NPs. Iron NPs improved efficiency of antioxidant system in blood and contributed to suppression of oxidative stress associated with tumor growth.
Differential association of 5-hydroxymethylcytosine levels with clinical and histopathological characteristics in breast cancer tumors.
Authors: Peña-Curiel Omar , Prada Diddiera , Otero Miguel , Díaz-Chávez José , Villarreal-Garza Cynthia , Justo Montserrat , Reynoso Nancy , Castro Hernandez Clementina , Cabrera-Galeana Paula , Bargallo-Rocha Enrique , Villaseñor-Navarro Yolanda , Caro-Sánchez Claudia , De La Garza Jaime G. , Herrera Montalvo Luis Alonso 
Published: September 2018

e23173 Background: Breast cancer is one of the top causes of cancer death worldwide. In Mexico, locally advanced breast cancer (LABC) comprises the majority of the breast cancer stages at diagnosis. Recent studies have suggested that 5-hydroxymethylcytosine (5hmC), could be a prognostic marker in breast cancer. However, the role of 5hmC on clinical and histopathologic characteristics in LABC has not been explored. Methods: From a cohort of locally advanced and advanced breast cancer patients treated at the National Cancer Institute in Mexico City with a 3-year follow-up, we measured 5hmC levels by immunodetection from fresh frozen tissue samples taken from the initial biopsy (N = 193). We determined the association between 5hmC levels and the most relevant clinical and histopathological characteristics. Results: From the full cohort analyzed; 42% were luminal A (n = 82), 33% were luminal B (N = 63), 9% were HER2-positive (N = 18), and 15% were triple-negative tumors. We found higher levels of global 5hmC in HER2 positive tumors vs. all other subtypes (p = 0.028, Kruskal-Wallis test). In luminal B tumors, 5hmC levels were associated with Ki67 (β = -0.04, 95%CI: -0.08, -0.01, p = 0.01 from multivariable model) but not in luminal A. Furthermore, we found that low 5hmC levels were associated with higher histological grade in HER2-positive tumors (p = 0.03, Kruskal-Wallis test). In subgroup analysis of LABC patients, we found higher 5hmC levels in non-ductal vs. ductal invasive tumors (β = 1.38, 95%CI: 0.049, 2.911, p = 0.043 from multivariable model). Also, lower 5hmC levels were associated with Ki67 (β = -2.53, 95%CI: -4.32, -0.74; p = 0.009 from multivariable model) and with histological type (p = 0.028, Kruskal-Wallis test) in LABC luminal B tumors. A borderline association with OS (p = 0.07, log-rank test) and RFS (p = 0.071, log-rank test) was observed in luminal A tumors in the LABC group. Conclusions: Our findings suggest that 5hmC levels are differentially associated with distinct clinical and histopathological characteristics in breast cancer, especially those linked to aggressiveness, including Ki67, histological type, and grade.
Evaluation of the prognostic value of the OncoMasTR RNA panel in diverse tumor types.
Authors: Moran Bruce , Lanigan Fiona , Russell Niamh , Barron Stephen , Wang Chan-Ju , Jirstrom Karin , Bracken Adrian P. , Gallagher William M. 
Published: September 2018

e23201 Background: Master transcriptional regulators (MTRs) are genes that are highly connected with many other genes and which can contribute to a specific cellular phenotype. The OncoMasTR panel, a set of 10 proliferation-linked MTRs and the key regulator of senescence CDKN2A, was identified in lymph node-negative breast cancer patients using publicly available data (Lanigan et al FEBS 2015 10.1111/febs.13354). Using two prognostic gene signatures and an experimentally defined ‘proliferative’ signature, highly concordant results for the top ranking sets of MTRs were found. One advantage of this process was the distillation of gene signatures into a discrete, mechanistically anchored biomarker set shown to be prognostically relevant, particularly in ER-positive patients, and with an ability to discriminate patients into low versus high risk of recurrence. Our aim here was to determine if the OncoMasTR panel was similarly useful in multiple other cancer types using publicly available transcriptomic data. Methods: The Gene Expression Omnibus was queried for datasets with relevant overall-, disease free- and/or recurrence free-survival information alongside microarray gene expression data. Survival analysis was conducted on 34 datasets using the R statistical environment package ‘survival’. Patient samples were scored based on median or tertile expression which were summed to give a final OncoMasTR RNA score, used to divide the patient samples into two groups (low and high risk) for analysis. Results: Using all 2,047 possible combinations of genes, a total of 23 datasets had significant prognostic associations. Following appropriate correction via multiple testing, this was reduced to 4 datasets representing bladder, lung and colorectal cancers, and multiple myeloma. Hazard ratios for the top 100 combinations in each data set were 1.8 – 2.1, 1.6 – 1.9, 1.1 – 1.3, 1.3 – 1.5 (standard error ±0.2, 0.1, 0.2, 0.1) respectively. All genes were found in the top ten combinations in all 4 datasets, and no specific combination was found to be prevalent across datasets, indicating that every MTR in the OncoMasTR panel contributes to its utility. Conclusions: The OncoMasTR panel is potentially prognostically useful in multiple cancer types.
Copy number variants signature in two patients with relapsed acute promyelocytic leukemia.
Authors: Nanni Jacopo , Marconi Giovanni , Fontana Maria Chiara , Papayannidis Cristina , Lo Monaco Silvia , Baldazzi Carmen , Padella Antonella , Simonetti Giorgia , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Testoni Nicoletta , Abbenante Maria Chiara , Paolini Stefania , Franchini Eugenia , Ottaviani Emanuela , Martinelli Giovanni , Bertamini Luca 
Published: September 2018

e23207 Background: Nowadays, Acute Promyelocytic Leukemia (APL) is a disease entity with a very high rate of cure and an estimated 2-year overall survival of 97%. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure, and relapse is a very rare occurrence. Methods : We collected data of all the APL referred to our institution from 2014. Within 23 patients, we encountered 20 new diagnosis and 2 relapse of APL. We analyzed blasts in samples obtained from Bone Marrow with Single Nucleotide Polymorphisms Array Cytoscan HD. Results: We compared copy number alterations in both relapsed patients with alterations detected in the pool of 20 newly diagnosed APL and we found specific signatures of CNVs for each patient. There were several copy number alterations related to each patient: the first patient presented gain of ROBO2, GRIP1, CTNNB1, SOX6, PBX1, GRIK2, CDKAL1 and loss FAF1, CREBBP, SBF1; the second patient presented gain of ROBO1, MAPK10, CADPS2, APBA1 and loss of GRIP1 and MYB. Subsequently we focused our attention on ROBO and GRIP1genes because they were alterated in both relapsed patients: ROBO proteins are associated to K channels while GRIP1 is involved in various critical functions, for example in androgen receptor binding, beta-catenin binding, glucocorticoid receptor binding, and it is also a regulator of glutamate metabolism, a well-known pathway in Leukemic Stem Cells. Conclusions: APL relapse is a very rare entity, and it is announced to become rarer with the advances in first line therapy. Molecular characteristics are hard to analyze without an effort to collect and bank samples together from multiple institutions. Since relapses, especially relapses out of follow-up period, represent a sudden life-treating condition for patients, to predict patients at higher risk of relapse we selected two candidate genes that could be involved in pathways favoring relapse. By the analysis of ROBO 1-2 and GRIP1 at the diagnosis of APL we could establish a different and strict follow-up program for patients with these alterations. Acknowledgement: ELN,AIL,AIRC,prog. Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project,HARMONY.
Overexpression of satellite alpha transcript in breast cancer patients to impair specific chromosomes.
Authors: Ichida Kosuke , Suzuki Koichi , Kakizawa Nao , Fukui Taro , Takayama Yuji , Watanabe Fumiaki , Kato Takaharu , Saito Masaaki , Futsuhara Kazushige , Rikiyama Toshiki 
Published: September 2018

e23216 Background: Impairment of stability in chromosomal structure facilitates abnormal segregation of chromosomes, increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation in the centromere region of chromosomes, which is associated with heterochromatin structures. Insufficient methylation, or demethylation, results in chromosomal instability. Satellite alpha transcript (Sat-A) is non-coding RNA transcribed from satellite alpha repetitive sequences at centromere, which is overexpressed by demethylated status of centromere. We have reported that increased levels of Sat-A were observed in patients with colorectal cancer, resulting in chromosomal instability. Difference levels of demethylation were reported in breast cancer patients but their association with Sat-A expression and chromosomal instability are not well known. In this study, we determined if Sat-A was involved in the chromosomal instability of breast cancer. Methods: We constructed lentiviral vectors expressing Sat-A and control viruses, which were infected in human mammary epithelial cells. The expression levels of Sat-A were determined by qRT-PCR and copy number alterations were evaluated by array CGH. Demethylation levels of satellite alpha sequences were determined by Methylight PCR. Then, these results were verified by using clinical specimens of 45 breast cancer patients. Results: Array CGH analysis revealed that copy number alterations were frequently seen at specific chromosomes of 8q and 20q in infected cells, despite no alteration in control, which was consistent with results in the clinical specimens. Patients with high levels of Sat-A expression showed more alterations than patients with low. Regression analysis exhibited that levels of Sat-A expression were significantly collated with demethylation levels of satellite alpha sequences. Conclusions: Overexpression of Sat-A impaired stability of chromosome 8q and 20q in human mammary epithelial cells, which was also recognized in clinical specimens of breast cancer patients. Chromosomal instability induced by Sat-A is involved in the development of breast cancer.
SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors.
Authors: Baselga Jose , Cortés Javier , DeLaurentiis Michelino , Dent Susan , Diéras Véronique , Harbeck Nadia , Hsu Jerry Y. , Jin Huan , Schimmoller Frauke , Wilson Timothy R. , Im Young-Hyuck , Jacot William , Krop Ian E , Verma Sunil 
Published: September 2018

TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.