bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of two BRM promoter variants on the risk of stage I/II upper aerodigestive tract cancers.
Authors: Wong Kit Man , Qiu Xiaoping , Cheng Dangxiao , Azad Abul Kalam , Palepu Prakruthi R. , Mirshams Maryam , Patel Devalben , Chen Zhuo , Roberts Heidi , Knox Jennifer J. , Wong Rebecca , Darling Gail Elizabeth , Waldron John N , Goldstein David P , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Der Sandy , Reisman David , Liu Geoffrey 
Published: March 2020

10522 Background: BRM is a key subunit of the chromatin remodeling complex SWI/SNF and a putative tumor suppressor gene that is silenced in 15-20% of many solid tumors (PMID 15722796). Evidence suggests that it is epigenetically regulated, as two BRM promoter insertion variants (BRM-741 and BRM-1321) may lead to gene silencing by recruiting histone deacetylases. The presence of both homozygous BRM-741 and BRM-1321 highly correlate with loss of BRM expression and function in lung tumors, while increasing smoking-related lung cancer by two-fold (PMID 21478907). Also, the pharmacologic reversal of epigenetic changes of BRM offers a potential novel therapeutic approach (PMID 21478905). We assessed whether these BRM variants are associated with the risk of upper aerodigestive tract cancers, focusing on Stage I/II tumors that would most benefit from new screening and prevention strategies. Methods: BRM was genotyped by qPCR using TaqMan probes. 1,008 controls were matched to 595 cases by frequency distribution based on age, gender and smoking status. Multivariate logistic regression generated adjusted odds ratios (aOR). Results: The 595 cases were: 115 esophageal, 278 lung, and 202 head and neck cancers. 51% were adenocarcinomas; 60% were Stage I. The frequency of homozygozity was: BRM-741, 26%; BRM-1321, 23%; both variants, 15%. In the combined analysis, there was significant correlation between malignancy and homozygous BRM-741 (aOR 1.91 (95%CI 1.3-2.4); p=0.001) or BRM-1321 (aOR 1.94 (95%CI 1.4-2.7; p=3x10E-4). Being homozygous for both BRM variants carried an even greater risk (aOR 2.45 (95%CI 1.6-3.9); p=1x10E-5). This correlation was similar for adenocarcinomas (aOR 2.53 (95%CI 1.4-4.2); p=6x10E-4) and squamous cell carcinomas (aOR 2.33 (95%CI 1.3-4.4); p=8x10E-4). The increased cancer risk was also similar between these subgroups: head and neck, esophageal and lung cancers; Stage I and II patients; smokers and non-smokers. Conclusions: The two homozygous BRM variants increase the risk of early stage upper aerodigestive tumors by more than two-fold independent of smoking status. BRM promoter variants and their potential epigenetic effect may be early events in the evolution of these cancers.
Prospective study of oncogenic mutations in circulating cell-free DNA (cfDNA) using a multiplex sequencing platform for patient (pt) allocation to phase I clinical trials.
Authors: Ong Michael , Mateo Joaquin , Pope Lorna , Mulick Cassidy Amy , Yap Timothy Anthony , Perkins Geraldine , Riisnaes Ruth , Flohr Penelope , Thway Khin , Saeed Sadiya , Denholm Katie Ann , Toloui Helen Nicole , Moran Kirsty , Lewis Jen Kate , Corral Jaime Jesus , Biondo Andrea , Molife L Rhoda , Kaye Stanley B. , Banerji Udai , De Bono Johann Sebastian 
Published: March 2020

10525 Background: Studies suggest that tumoral cfDNA can be isolated from plasma and used as a biomarker. Methods: We conducted a prospective study in adult pts with advanced cancer referred for phase I clinical trials Sep09-Dec10 (A: Pilot Phase n=104) and Jan11-Sep11 (B: Expansion Phase n=176). cfDNA and tumor DNA from formalin-fixed paraffin-embedded (FFPE) tissue were isolated, quantified, and analyzed for 238 mutations in 19 oncogenes by the Sequenom OncoCarta Panel 1.0. Mutation data were used for trial allocation when available. Pt data and outcomes were collected. Statistical inferences used Wilcoxon rank-sum and Pearson’s Chi-squared. Results: 280 pts enrolled including breast (60), colorectal (42), ovarian (37), lung (31), and prostate (20); median age 60yrs [23-81]; 93% ECOG PS 0-1. cfDNA in 95% and FFPE in 60% were analyzed. Median time to cfDNA result, trial allocation and consent were 7 [5-14], 6 and 23 d. Median cancer pt cfDNA concentration (ng/ml) (A: 18 [1-1600]; B: 34 [16-1657]) was higher than 20 healthy volunteers (6 [5-13] A: p=0.0001) and higher in metastatic vs locally advanced cancer (A: 21 vs 4 p=0.0006; B: 42 vs 24 p=0.066). Pts with higher than median [cfDNA] had shorter median survival (MST) than below (A: 217 vs 274 d, HR 1.72 95% CI 1.07-2.65, p=0.025; B: MST not reached yet). Mutations were found in 89 pts (32%), including KRAS (11%), PIK3CA (5%), MET (5%), BRAF (4%), and AKT (2%). cfDNA mutations (57 pts, 21.5%) were mainly found above the median [cfDNA] (A: 41 vs 17% χ2=6.9, p=0.009; B: 24 vs 11% χ2=5.0, p=0.025). Of 155 pts with both cfDNA and FFPE available, 68 had mutations detected: 30 identical in cfDNA and FFPE; 28 in FFPE alone and 10 in cfDNA alone. Overall, 153 pts were treated on a phase I trial; 23 pts had relevant mutation data and received a trial targeting the PI3-Akt-mTOR axis. Conclusions: Higher cfDNA is associated with greater disease burden, worse prognosis, and higher mutation detection rate, suggesting cfDNA is tumorally derived. Moreover, cfDNA can be analyzed for oncogenic mutations in a time-frame suitable for clinical decision making, making it a potentially useful non-invasive adjunct to tumour DNA analysis.
Isolation of circulating tumor cells using a novel EMT-based capture method.
Authors: Bitting Rhonda Lynn , Boominathan Rengasamy , Rao Chandra , Embree Elizabeth , George Daniel J. , Connelly Mark C. , Kemeny Gabor , Garcia-Blanco Mariano , Armstrong Andrew J. 
Published: March 2020

10533 Background: Circulating tumor cells (CTCs) have potential prognostic, predictive and surrogate implications in oncology. In patients with metastatic castration-resistant prostate cancer (CRPC) and breast cancer (BC), we have shown that CTCs isolated using epithelial cell adhesion molecule (EpCAM) ferromagnetic capture express mesenchymal markers, including N- and O-cadherin, suggesting phenotypic plasticity and the presence of epithelial-mesenchymal transitions (EMT). Therefore, we postulate that during metastasis, tumor cells exist as a spectrum of epithelial to mesenchymal phenotypes and may not be captured with existing EpCAM-based CTC technology. The goal of this study is to identify CTCs in CRPC and BC patients using a novel mesenchymal-based capture method. Methods: In patients with advanced CRPC and BC, two EDTA and one CellSave tube of blood are collected. Using the CellSearch system (Veridex, USA), CTCs are captured with either anti-N-cadherin (N-cad) or anti-O-cadherin (O-cad) ferrofluid and detected cells (events) are defined as beta-catenin and DAPI positive, CD45 negative intact cells. We evaluated the performance of these EMT-based ferrofluids in healthy volunteers, control cells, and in a pilot study of patients with CRPC, and compared enumeration of cells using novel vs. standard EpCAM-based capture methods. Results: In healthy volunteers, rare events were detected using the novel capture methods. In CRPC patients, O-cad capture detected more events in 3 of 5 subjects than EpCAM-based capture, and the majority of captured cells were cytokeratin negative. See table below. Conclusions: These preliminary results suggest that a novel CTC phenotype exists in CRPC based on EMT properties, particularly overexpression of O-cadherin. Further characterization of these cells from patients with advanced PC, BC, and other solid tumors will provide insight into EMT and metastasis biology. [Table: see text]
DJ-1 as a predictor of pathologic complete remission of neoadjuvant chemotherapy with breast cancer patients.
Authors: Kawate Takahiko 
Published: March 2020

10544 Background: DJ-1 is a multifunctional protein which is encoded by the causative gene of familial Parkinson disease (i.e., PARK7), and is associated with carcinogenesis. DJ-1 is also a candidate marker for the presence of breast cancer cells, in which it is secreted in nipple fluid and serum. We previously reported that a DJ-1 expression pattern that is low at the protein level and high at the mRNA level is associated with DJ-1 secretion. This secretory expression pattern correlated with a negative hormone receptor status and with unfavorable clinical outcome in breast cancer patients. However, the association of the DJ-1 secretion pattern with therapeutic effect has yet to be determined. Methods: A total of 299 patients received neoadjuvant chemotherapy and surgery from 2002 to 2010 at our institution. We performed immunohistochemistry and in-situ hybridization of DJ-1 in both the needle biopsy and operative specimens of 147 cases with a follow-up time of 3.1 years. The average degree of staining intensity was evaluated semi-quantitatively using an image analyzer. Univariate and multivariate analyses were used to evaluate the predictive value of the therapeutic effect of neoadjuvant chemotherapy. Results: A low expression of DJ-1 protein was detected in the needle biopsy and operative specimens of 89 of the 147 cases, regardless of a high or maintained mRNA level. The tumor response was evaluated as pathological complete remission (pCR) in 39 cases and as non-pCR in the remaining 108 cases. A low expression of DJ-1 protein, which was detected in 34 (87.2%) pCR cases, was a significant predictor on univariate analysis (P <0.001). On multivariate analysis, a low expression of DJ-1 was shown to be a significant independent predictor similar to established predictors such as estrogen receptor status and human epidermal growth factor receptor 2 score. Conclusions: A low expression of DJ-1 protein can serve as a novel and important predictor of a neoadjuvant chemotherapeutic effect, as well as a promising indicator for serologic diagnosis in breast cancer patients.
Evaluation of CYP3A5, VEGF-a, and VEGFR2 polymorphisms as markers of sunitinib toxicity.
Authors: Rodriguez de Antona Cristina , Grande Pulido Enrique , Leandro-Garcia Lj , Barriuso Jorge , Capdevila Jaume , Jimenez Paula , Castelo Beatriz , Castellano Daniel E. , Longo Federico , Garcia-Donas Jesus 
Published: March 2020

10546 Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma (RCC), GIST and pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism in Sun metabolizing gene CYP3A5, was associated with an increased risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in VEGF-A and VEGFR2 were suggested to increase the risk of hypertension (HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These data have not been validated so far. We aim to assess the value of these polymorphisms as markers of tox using a wide range of solid tumors treated with Sun. Methods: In this non-interventional and retrospective study, DNA was collected from 28 patients with different pathologies (16 pNETs, 5 medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1 carcinoid of the rectum) treated with Sun in a daily practice setting. Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C>A (rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations between the genotypes and Sun dose reductions and HT were performed using univariable analyses. Results: In agreement with previous reports, we found that VEGF-A rs699947 conferred a statistically significant increased risk of developing HT during treatment (HR=9.8, 95%CI=1.2-82.0, P=0.034). CYP3A5*1 high metabolizing allele showed a trend towards the increase in the risk of Sun dose reductions due to tox (HR=2.4, 95%CI=0.8-6.8, P=0.11) with a median time to dose reduction of 7.0 months for wild type homozgygous patients and 4.6 months for heterozygous patients. A trend was also found on the relation between VEGF-A rs699947 A/A patients (HR=3.8, 95%CI=0.8-16.8, P=0.080) and dose reduction risk. No significant associations were found for VEGFR2 rs1870377. Conclusions: The present study suggests that VEGF-A rs699947 is a risk factor for Sun HT and has a role in other tox leading to dose reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk of Sun dose reductions. If confirmed, these markers could be used to identify a subset of patients with an increased risk of Sun toxicity.
Pharmacogenetic predictors of adverse events in stage II-III colon cancer (CC) patients treated with oxaliplatin and fluoropyrimidines-based adjuvant chemotherapy (CT): A GEMCAD study.
Authors: Custodio Ana , Moreno Juan , Aparicio Jorge , Gallego Plazas Javier , Fernandez-Martos Carlos , Yaya Ricardo , Calatrava Ana M , Maurel Juan , Burgos Emilio , Tejerina Eva , Barriuso Jorge , Moreno Victor , Martinez Marín Virginia , De Castro Javier , Lamarca Angela , Lapunzina Pablo , Madero Rosario , Cejas Paloma , Feliu Jaime ,   Grupo Español Multidisciplinar de Cáncer Digestivo (GEMCAD)
Published: March 2020

10547 Background: Although the benefit of oxaliplatin-based adjuvant CT has been demonstrated in patients with resected stage II-III CC, the recommendation to administer postoperative treatment must consider its potential adverse events. Predicting individual patients’risk of severe toxicity could potentially improve the quality of care by allowing individualization of treatment. We investigate the utility of determining single nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin and fluoropyrimidines metabolisms to predict the toxicity of adjuvant CT in stage II-III CC patients. Methods: DNA was extracted from formalin-fixed paraffin-embedded samples from 379 surgically treated high-risk stage II (27.71%) and stage III (72.29%) CC patients receiving adjuvant CT (54.35% FOLFOX, 45.65% XELOX) from January 2004 to December 2008. Genotyping was performed for 35 SNP in 18 genes using the MassARRAY (SEQUENOM) technology. Results: A total of 89 (23.4%) patients experienced at least one grade 3-4 adverse event. The most common grade 3-4 toxicities were neutropenia (15.3%), diarrhea (8.17%) and neurotoxicity (7.65%). The MTHFR rs1801133 C>T C/C (30.1% C/C, 17.5% C/T, 21.7% T/T; p=0.043) and XRCC2 rs3218408 T>G T/T (28.3% T/T, 16.2% G/T and 10% G/G; p=0.007) genotypes were associated with higher risk of any grade 3-4 toxicities, whereas the incidence of severe toxicity was lower in patients with the UMPS rs3772807 G>C C/C (14% C/C, 21% C/G, 28.9% G/G; p=0.021) and DPYD rs970337 G>A A/A (16.7% A/A, 21.1% A/G, 30.1% G/G; p=0.028) genotypes. In addition, the DPYD rs970337 G>A A/A genotype was associated with a lower rate of grade 3-4 diarrhea (5% A/A, 9.4% A/G, 8.1% G/G; p=0.030), the ABCG2 rs3114018 A>C C/C genotype with an increased rate of grade 3-4 neutropenia (15.2% C/C, 6.3% A/C, 4.5% A/A; p=0.034) and the ERCC1 rs11615 T>C T/T genotype with a lower rate of grade 3-4 neurotoxicity (5.4% T/T, 9.1% C/T, 10.2% C/C; p=0.032). Conclusions: Our data suggest that SNPs in genes involved in oxaliplatin and fluoropyrimidines metabolisms can potentially predict severe toxicity in stage II-III CC patients treated with adjuvant CT.
Use of gene expression and alternative splicing signatures to discriminate breast cancer stem cells from fibroblasts.
Authors: Weaver David T. , Shapiro Irina M , Derr Alan G , Paterson Daniel , Pachter Jonathan A 
Published: March 2020

1057 Background: Tumors frequently contain cancer stem cells (CSCs) or tumor-initiating subpopulations, with an ability to self-renew and regenerate all cell types within the tumor. Basal-like breast cancers exhibit features of CSCs, including expression of surface markers, even though these cells are rare. Given the role of CSCs in the recurrence and spread of cancer, there is an urgent need to develop new therapeutic agents that target CSCs. Development of CSC-targeted drugs will be greatly facilitated by biomarkers that can identify CSCs to aid in patient selection and determination of drug response. Defining the CSCs in tumors is complicated by the high mesenchymal nature of fibroblasts. Analysis of gene expression and alternative splicing patterns in CSCs that are not observed in fibroblasts may provide valuable new CSC-specific markers. Methods: Alternative splicing and gene expression microarray strategies were used to identify selected exons and differentially expressed genes between 10 Basal human breast cancer cell lines and a combination of 12 Luminal and 3 fibroblast cell lines. Q-PCR analysis was conducted to determine candidate CSC gene differential expression between Basal, Luminal, and Fibroblast cells lines. Results: Expression levels of 11 genes were higher and 24 genes were lower in the Basal cell lines versus Luminal or fibroblastic cell lines. Comparison of Basal cell lines to the Luminal/Fibroblast cell lines identified 36 cassette exons that were included, and 26 that were excluded in Basal cell lines. Also, 19 genes were upregulated in Basal cell lines compared to the other groups as detected by Q-PCR. Interestingly, the 19-multigene model defined the Triple Negative Breast Cancer patients that were Likely to Recur under standard chemotherapy with a p = 1.90e-03 and AUC 0.723. Conclusions: Gene and exon marker sets distinguish CSC versus fibroblasts and may be instructive in identifying patients that recur early in Triple Negative Breast Cancer. The CSC-associated RNA signatures identified here will be further refined to develop new CSC-specific diagnostic markers to stratify breast cancer patients and monitor response to novel CSC-targeted therapies.
FDG-PET and CT as early predictors of outcome in NSCLC patients treated with erlotinib.
Authors: Iannone Robert , Evelhoch Jeffrey L. , Lam Raymond , Bergstrom Donald Alan , Thornton Bob , Herman Gary A. , Mozley P. David 
Published: March 2020

10573 Background: Tumor metabolism as assessed by FDG-PET is an early biomarker for clinical benefit in oncology. This multi-national study evaluated associations of changes in mean standardized uptake values (SUVmean) of FDG and tumor burden with disease control rates (DCR: CR+PR+SD), PFS and OS in 48 NSCLC patients (EGFR mutants or favorable clinical/demographic characteristics) treated with erlotinib. The primary hypothesis was that changes in SUVmean at day 8 predicted DCR. Methods: Patients were scanned by FDG-PET (twice pre-therapy, 1 and 3 weeks post-therapy) and CT (same as FDG-PET and every 6 weeks post-therapy until progression or death). Early response biomarkers included the decrease in SUVmean (DiSUV), sum of diameters (DiSOD) and sum of volumes (DiSOV). For the primary hypothesis, metabolic response (MR) was defined as a decrease of >2SD the variability between baseline PET scans (30%). Exploratory analyses of the biomarkers at various thresholds were performed. Results: The primary hypothesis was met: DCR was 34.6% (80% CI: 17.5%, 48.2%) higher in patients with a MR at day 8 (p = 0.033); the association was stronger for day 22. The table compares hazard ratios derived from the "optimal" % decrease (smallest upper 80% confidence limit) over the 10% to 50% (by 10%) range for all biomarkers and time points, by PFS and OS. Conclusions: FDG-PET was predictive for clinical responses after 8 days of treatment. Comparing all biomarkers, DiSOV had stronger associations than both DiSUV and DiSOD with PFS or OS. For NSCLC treated with erlotinib in this clinical context, the decrease in CT-based tumor volume may be a better early predictor of clinical outcome than FDG-based SUVmean. [Table: see text]
Preoperative detection of circulating tumor cells in patients with colorectal carcinoma: Correlation with clinicopathologic variables and recurrence.
Authors: Sakihama Hideyasu , Kobayashi Nozomi , Funakoshi Tohru , Shimokuni Tatsushi , Homma Shigenori , Takahashi Norihiko , Kataoka Akihiko , Ozaki Michitaka , Kamiyama Toshiya , Taketomi Akinobu 
Published: March 2020

10578 Background: The role of circulating tumor cells (CTC) in the management of colorectal cancer patients has not fully established. The aims of this study are to investigate the relationship between the presence of CTC with clinicopathological variables and recurrence by magnetic activated cell sorting (MACS) system. Methods: Peripheral blood samples were collected from 80 patients. Enrichment of CTC was performed by direct immunomagnetic labeling of EpCAM positive cells in peripheral blood. Subsequently, double immunofluorescence for cytokeratin and CD45 was performed to detect CTC. Peripheral blood samples from twenty healthy volunteers were used as controls. Results: Preoperative positive rate of CTC was 35% while specificity was 100%. No CTC was found in peripheral blood from healthy volunteers. No correlation was found between the presence of CTC and location of tumors, grade of differentiation, vessel invasion, lymph node metastasis or TNM stages. On the other hand, the depth of invasion (0% in Tis, 11.1% in T1, 18.2% in T2 and 34.7% in T3+T4, P=0.05) and tumor recurrence (28.2% for initial operation and 88.9% for reoperative surgery for tumor recurrence, P<0.001) closely correlated with the presence of CTC. Preoperative positive rate of CTC among patients who have recurred postoperatively was 75%. Conclusions: Our results indicate that detections of CTCs correlate with the depth of invasion and tumor recurrence. Preoperative presence of CTCs might be a strong predictor for tumor recurrence.
Antigens diagnoses in paraneoplastic neurological syndromes.
Authors: Rudnicka Halina , Jagiello Gruszfeld Agnieszka I. , Glogowska Iwona 
Published: March 2020

10582 Background: At present, paraneoplasmatic neurological syndroms (PNS) are thought to be autoimmunological disorders. Neurological symptoms in PNS result from the disturbance of the nervous system, with a participation of the immune response triggered by the aberrant expression of the so-called onconeuronal antigens of a tumour. Very important for PNS diagnostics is the investigation of antineuronal antibodies (ANA) in the serum. Different types of ANA are frequently associated with specific tumors and with specific neurological syndromes.Investigations of serum ANA in patients with breast cancer with the symptoms of PNS. Methods: Investigations of ANA in serum were performed with the indirect immunofluorescence test but the type of ANA was analyzed by the Western Blot (WB) method . The presence of these antibodies which are included to the group of “the so called well characterized” is believed to be a definite (95 – 100%) determinant of the PNS diagnosis. Results: We examined 147 patients with breast cancer suspected to have PNS, hospitalized at Breast Cancer Clinic of the Institute of Oncology in Warsaw. The immunofluorescence test was positive in 92 patients, however in 24 patients the WB occurrence of “the well characterized” antibodies was found. In this group we observed: in 4 patients the cerebellar degeneration (anti-Yo, anti-Ma2); in 6 patients brainstem encephalitis and encephalomyelitis combined with sensory neuropathy (anti-Ma2, anti-CV2, anti-Yo, anti-Hu, anti-Ri); 4 myastenic syndrome (anti-Hu,anti-Ri,anti-Ma2/Ta); 5 sensory neuropathy (anti-Hu, anti-Yo, anti-Ma2, anti-Ri); and in single cases we also observed polyneuropathy: Guillain-Barre (Ma2): Miller-Fisher syndrom (anti-Ma2/Ta); cancer-associated retinopathy (anti-Yo); dermatomyositis (anti-Ri) and scleroderma (anti-Yo). Conclusions: Our analysis indicates that the investigation of the presence of ANA in the serum is the important in the diagnosis of PNS in patients with breast cancer. The types of ANA correspond to the individual paraneoplastic neurological syndromes which opens the proper methods of treatment in PNS.