bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comprehensive comparison of circulating tumor cell capturing technologies by apheresis of cancer patients.
Authors: Stratmann Antje , Fischer Johannes C. , Niederacher Dieter , Raba Katharina , Schmitz Arndt , Kim Phillip Sangwook , Singh Sharat , Stoecklein Nikolas H. , Krahn Thomas 
Published: March 2020

e21017 Background: Obtaining tumor tissue from cancer patients for diagnosis and biomarker assessment for patient selection is challenging. Circulating tumor cells (CTCs) may represent an attractive alternative as a “liquid biopsy”. However, capturing these rare cells from whole blood is a major challenge that still needs significant improvement. Here we present preliminary data of an ongoing study comparing different CTC capturing technologies. Methods: A collaboration network between Bayer Pharma AG, the University of Düsseldorf as clinical partner and providers of CTC capture methods was established. In addition logistics were organised to guarantee a fast and reliable sample transfer. For optimal comparison, CTC preparations from the same patient were used. The required high amounts of sample aliquots and CTCs was obtained by apheresis. Breast and pancreatic cancer patients (non- and metastatic) were enrolled. Blood samples were obtained, as well as buffy coat by apheresis. Samples were shipped within 48 h to partner companies for CTC analysis. At two sites the CellSearch system by Veridex was performed. Today’s standard was compared with another antigen-based method, a filter method and an approach depending on electrophysiological properties. Downstream analysis of the isolated CTCs was performed at Prometheus using their sensitive immunoassay. Results: Significantly higher CTC amounts were detected in buffy coats obtained by apheresis in comparison with CTC counts obtained from a blood draw. In contrast to the blood samples, all methods were able to detect CTCs in buffy coats from both non-metastatic and metastatic cancer patients. The included novel approaches showed in general a better yield of CTCs in comparison to CellSearch. Downstream analysis revealed individual signalling pathway activity profiles. Conclusions: Apheresis is a suitable procedure to capture high amounts of CTCs and therefore to enable an optimal technology comparison. The isolated CTCs are viable and stimulatable. The preliminary results of our study show that an improvement in CTC capturing is taken place, indicating an important step forward regarding the use of CTCs as “liquid biopsy” in a clinical setting.
Capture of EpCAM-negative and vimentin-positive circulating cancer cells (CCCs) from blood of metastatic breast cancer patients using ApoStream.
Authors: Neal Christopher , Sukumaran Sujita , Gupta Vishal , Jafferji Insiya , Hasegawa Dave , Melnikova Vladislava O. , Davis Darren W. 
Published: March 2020

e21029 Background: Up-regulation of epithelial mesenchymal transition (EMT) and the reduction of epithelial marker expression is associated with invasion, cancer progression, resistance to conventional therapies and poor prognosis. ApoStream, a novel continuous flow dielectrophoresis field-flow fractionation (DEP-FFF) device, was used to enable antibody-independent capture of circulating cancer cells (CCCs,also referred to as circulating tumor cells, CTC) for subsequent phenotyping of EMT markers. Methods: A side-by-side comparison of CellSearch and ApoStream was performed on 10 metastatic breast cancer patients. A multiplexed immunofluorescent assay and laser scanning cytometry analyses were used to unambiguously identify CK+/CD45–/DAPI+ CCCs and quantify their EpCAM and vimentin expression. Results: ApoStream recovered CK+/CD45–/DAPI+ CCCs from each breast cancer patient sample tested (mean=255 CCCs per 7.5 ml blood, see Table). ApoStream consistently recovered significantly higher number of CCCs compared to CellSearch (p=0.024). ApoStream recovered both EpCAM+ and EpCAM– CCCs in 50% and 90% of patients, respectively. Vimentin+ CCCs were isolated from 90% of patients. Conclusions: ApoStream’s higher capture efficiency demonstrated the majority of CCCs from breast cancer patients were EpCAM negative and vimentin-positive. ApoStream technology can be used to monitor CCCs undergoing EMT. [Table: see text]
Practice patterns in the use of adjuvant therapy for post-menopausal early-stage breast cancer in the pre- and post-Oncotype DX era.
Authors: Latif Asma , Small Alexander C. , Moshier Erin L. , Adelson Kerin B. , Raptis George , Godbold James H. , Oh William K. , Galsky Matt D. 
Published: March 2020

e21032 Background: Personalized oncology offers the promise of selectively applying therapeutics to patients most likely to benefit, while sparing those unlikely to benefit from potentially toxic therapies. Oncotype DX is a 21-gene assay utilized to identify hormone-receptor positive (HR+), node negative, breast cancer (Br CA) patients who may be successfully treated with adjuvant hormonal therapy alone. We hypothesized that practice patterns with adjuvant therapy have changed since the commercial availability of Oncotype DX in 2004. Methods: The Public National Cancer Database was queried to identify patients age ≥ 50 with stage I or II Br CA diagnosed from 2000 to 2008. Patients were classified by adjuvant therapy including hormone, chemotherapy, hormone and chemotherapy, and no hormone or chemotherapy. Log-binomial regression was used to estimate prevalence ratios for the proportion of patients receiving adjuvant therapies from 2000-2003 compared to 2004-2008. Results: 833,018 patients age ≥ 50 with stage I or II Br CA were identified. The application of adjuvant therapies for the periods pre- and post-availability of Oncotype DX are detailed in the Table. Conclusions: There has been significant increase (13%) in the use of hormonal therapy alone as adjuvant therapy for patients age ≥ 50 with HR+ stage I-II Br CA since commercial availability of Oncotype DX. While this has been slightly offset by a decrease in the use of chemotherapy plus hormonal therapy, there has been a larger decrease in the use of “no adjuvant therapy”. Data regarding predictive biomarkers should be captured by registries in an effort to determine the true impact of these tests on treatment utilization. [Table: see text]
HER3 expression in the primary tumor as marker of metastatic potential in breast cancer patients.
Authors: Berghoff Anna Sophie , Bago-Horvath Zsuzsanna , Preusser Matthias , Steger Guenther G. , Birner Peter , Zielinski Christoph , Bartsch Rupert 
Published: March 2020

e21033 Background: Breast cancer (BC) is the most common cancer related cause of death in women. Therefore, identification of novel prognostic markers is an important field of research. Recently, HER3 expression was postulated as risk factor for metastatic spread to the brain. We aimed to analyze the predictive value of HER3 expression in patients with metastatic BC treated between 1993 and 2010 at the Medical University of Vienna. Methods: Patients of each subtype (luminal, HER2 positive, triple negative) with metastatic breast cancer were identified from a breast cancer data base. Tissue of the primary tumor was raised from a breast cancer bio-bank. Immunohistochemical staining of estrogen-receptor, progesterone-receptor, HER2 and HER3 was performed. Chi2 test was used to correlate two factors. Overall survival (OS) and time to progression (TTP) were estimated using the Kaplan-Meier method. Results: A total of125 patients (39 luminal, 42 HER2 positive, 44 triple negative) with metastatic BC were available for this analysis. 71 patients (56.6%) had visceral metastases and 67 patients (46.4%) had brain metastases. 7.4% of specimens showed a positive, uniform, intense membranous staining of > 30% of invasive tumor cells (Her3 3+). Less intense, incomplete, membranous staining was observed in a further 34.4%. HER3 expression in the primary tumor did not correlate with BC subtype (luminal 12.8%; HER2 positive 2.4%; triple negative 6.8%; n.s.; Chi2 test). Furthermore, no correlation with the likelihood of developing brain metastases (5% vs. 9.8%; n.s.; Chi2 test) or visceral metastases (7.3% vs. 7.7%; p:n.s.; Chi2 test) was found. Counter intuitively, patients with HER3 overexpression in the primary tumor had a significantly longer TTP (21 vs. 47 months; p=0.03; log rank test) and a trend towards longer OS was observed as well (53 vs. 112 months; p=0.073; log rank test). Conclusions: In contrast to previous reports, we could not validate that HER3 expression predicts for metastatic potential in general and also with regard to brain metastases of BC in a population that was equally distributed between BC subtypes. Further studies are therefore needed to evaluate the prognostic value HER3 expression in BC.
Retrospective study of systemic chemotherapy in combination with consolidative stereotactic body radiation therapy (SBRT) in patients with five or fewer oligometastases from breast, colorectal, and lung cancers.
Authors: Ulhoa-Cintra Alice , Monga Dulabh K. , Kirichenko Alexander V. 
Published: March 2020

e21036 Background: The oligometastatic state is one of limited metastases, amenable to local therapies of curative potential. Stereotactic body radiation therapy (SBRT) is a non-surgical treatment with a primary goal of rapid local tumor control and low toxicity allowing prompt return to systemic therapy. Breast (BRC), colorectal (CRC) and non-small cell lung cancers (NSCLC) have oligometastases as first presentation. In these patients, consolidative SBRT offers effective local control and low toxicity, with the potential for improved survival benefit without affecting quality of life. We report our experience on such patients. Methods: 31 patients with BRC (9), CRC (16) and NSCLC (6) with ≤ 5 unresectable metastases to one to three organ sites were identified. Data were obtained from chart review. Primary end point was infield local control. Lesions with at least 6 months of radiographic follow-up were assessable. Secondary end points were toxicity and survival. Results: All patients completed SBRT to 38 lesions (≤2/patient). 29 received prior chemotherapy for metastatic disease. 14 were treated with at least 1 prior regimen and 15 at least 2 (0-8). At a median follow-up of 16 months (4-32), 22 patients (8 BRC, 10 CRC and 4 NSCLC) were assessable. At 6 months, 20 patients had infield local control and 3 demonstrated distant metastases. At 1 year, this was seen in 19 and 7 patients respectively. The most common toxicity was grade ≤2 fatigue. All BRC had infield local control at 6 months and 1 year. Among CRC, 9 had infield local control at 6 months and 7 at 1 year. 3 NSCLC patients had infield local control at 6 months and 1 year. No BRC demonstrated distant progression at 6 months; at 1 year, it was seen in 2 patients. 3 CRC had evidence of distant progression at 6 months and 1 year. 1 NSCLC patient had distant progression at 6 months and 2 at 1 year. 6 patients died from their underlying malignancy; the median survival for 5 of these patients was 20 months (5-34). Conclusions: The combination of systemic chemotherapy and consolidative SBRT is safe and effective for patients with oligometastatic disease
Modulation of angiogenic biomarkers in patients receiving high-dose TRC105.
Authors: Liu Yingmiao , Starr Mark , Brady John C , Pang Herbert , Dellinger Andrew , Leigh Bryan R. , Theuer Charles P. , Hurwitz Herbert , Nixon Andrew B. 
Published: March 2020

e21038 Background: TRC105, an anti-CD105 monoclonal antibody, has completed phase 1 testing and is being studied in multiple phase 2 trials. We previously reported that low dose TRC105 (0.01-1.0 mg/kg) modulated the expression of soluble angiogenic biomarkers in patients [J Clin Oncol 29: 2011 (suppl; abstr 10565)]. In this report, we evaluated angiogenic biomarkers in patients receiving higher doses of TRC105 including the recommended phase 2 dose. Methods: Patients with advanced refractory solid tumors were treated with escalating doses of TRC105 until disease progression. Serial plasma samples were analyzed via an optimized multiplex ELISA platform. 36 biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month (C2D1), concurrent with radiological restaging near the end of cycle 2 (C2D22), and at end of study (EOS). Results: 32 patients treated with TRC105 at doses of 0.3 to 15 mg/kg were evaluated for biomarker expression. Wilcoxon signed rank tests indicated that the following analytes were significantly different at C2D1 when compared with baseline (p<0.05): Ang-2, IGFBP-3, total PAI-1, PDGF-AA, PDGF-BB, TSP-1, VEGF-D were all down-regulated; and E-Cadherin, soluble CD105, E-Selectin, IL-6, OPN, TSP-2, vWF were all up-regulated. At EOS, significant increases from C2D1 were observed for the following analytes: Ang-2, CRP, ICAM-1, IGFBP-1, IL-6, TSP-2, and VCAM-1 (p<0.05). Additionally, dose-dependent increases in soluble CD105 at C2D1 were observed (p<0.0001, r=0.9), suggesting direct target modulation by TRC105. Conclusions: TRC105 therapy is associated with early down-regulation of certain key angiogenic biomarkers and a dose-dependent increase in sCD105. Increases in many initially down-regulated angiogenic factors were observed at the time of progression, suggesting possible mechanisms for acquired resistance to TRC105. Further analysis of TRC105 in specified patient populations is underway and may provide more insight into the biological effects of this drug.
Prognostic impact of circulating endothelial cell counts in patients with advanced non-small cell lung cancer.
Authors: DeJoubner Nutan Jyothi , Kang Hyunseok , Li Qunna , Harris Wayne A C , Stewart Rena , Price Alicia , Quyyumi Arshed , Kono Scott A. , Ramalingam Suresh S. , Owonikoko Taofeek Kunle , Khuri Fadlo Raja , Waller Edmund K. 
Published: March 2020

e21045 Background: Blood progenitor cells expressing the stem cell marker CD34 have been associated with prognosis in cancer. We hypothesized that non-small cell lung cancer (NSCLC) patients with higher numbers of circulating CD34+ endothelial progenitor cells (CD34+/CD146+/CD45-, CEC) would have worse post-treatment outcomes and patients with more hematopoietic progenitor cells (CD34+/CD45+/CD45dim/CD133+, HPC) would have better outcomes. Methods: Blood samples from patients with advanced NSCLC were analyzed at 3 time points: prior to chemotherapy, after cycle one, and at completion of treatment or progression of disease, in an IRB-approved protocol. CEC, HPC, and immune subsets were measured by flow cytometry optimized for rare event detection. Primary outcomes were progression and death from the time of study entry. Patients were categorized and compared for progression free survival (PFS) and overall survival (OS) based on median cell counts. Differences between groups were tested using log-rank test and Cox regression. Results: A total of 62 patients were enrolled with mean age of 64 (37-87 years). There were 29 deaths after a median follow-up of 8.1 months. 40 patients progressed at a median of 5.4 months. Median numbers of CEC, HPC, and CD4+ T-cells were (0.05/uL, 0.41/uL, and 637/uL, respectively). Lower CEC at baseline was associated with a favorable PFS compared to those with higher counts (median PFS of 7.3 months versus 4.3 months, p=0.049). In a multivariate analysis after adjusting for age, gender, smoking, race, TNM stage, pathology, performance status and CD4 counts at baseline, patients with high CEC had almost 3-fold risk of death (HR=2.70, p=0.04) and disease progression (HR=3.03, p < 0.01) compared with patients with low numbers of CEC. In the same model, patients with fewer CD4+ T cells had > 3 fold risk of death compared with patients with higher numbers (HR=3.79, p=0.01). HPC content was not associated with OS or PFS. Conclusions: In patients with advanced NSCLC, higher CEC and lower CD4 counts at diagnosis are associated with worse outcomes. Higher CEC may serve as a cellular biomarker for extent of disease or tumor biology. Patients with poor T-cell immunity prior to treatment have worse survival.
Variability of gene expression profile in breast cancer core biopsy: Impact on prognostic and predictive multigene signatures.
Authors: Jarzab Michal , Bal Wieslaw , Kowalska Malgorzata , Oczko-Wojciechowska Malgorzata , Kowal Monika , Rembak-Szynkiewicz Justyna , Dyla Alicja , Chmielik Ewa , Stobiecka Ewa , Bobek-Billewicz Barbara , Tarnawski Rafal 
Published: March 2020

e21049 Background: Gene expression profiling has been shown to be effective in the analysis of postoperative tumor samples in breast cancer. However, when small specimens like core biopsy samples are considered, the small size of the collected material makes it difficult to obtain high tumor percentage in the specimen. Thus, we tested the strategy of obtaining three independent cores for molecular analysis and assessed the influence of the stability of different prognostic and predictive signatures. Methods: We prospectively collected breast core biopsies from 82 consecutive patients treated by pre-operative chemotherapy. In each patient, three cores from different tumor areas were sampled for molecular testing, independent of the cores collected for histopathological analysis. RNA was isolated by QIAGEN RNeasy kits, gene expression profiling was carried out using Affymetrix HG-U133 Plus 2.0 microarrays. Results: In 27 patients, three independent specimens were analyzed by microarray gene expression profiling (in total 81 samples). When this training set was analyzed by unsupervised Principal Component Analysis, the overall concordance between the three tumor cores was observed, but no such concordance was seen for three tumors (for each with one significant outlier). When we assessed the set of chosen 20 prognostic and predictive signatures, we confirmed that the homogeneity of gene expression within the signatures is significantly better than for random sets of genes, but we observed the notable differences between the signatures. The heterogeneity decreased when genes with low between-patient variance were excluded; they also showed a higher intra-patient variability of gene expression. We also assessed the heterogeneity of single expression markers and furher validated our findings on an independent set of 55 patients. Conclusions: The use of three independent cores for gene expression testing in breast cancer may be a successful strategy to overcome tumor heterogeneity and sampling error and result in more stable results of prognostic and/or predictive signatures. Supported by Polish National Science Center grant N402 6861 40
Determining the metastatic potential of circulating tumor cells.
Authors: Menen Rhiana , Pinney Emmett , Kolostova Katarina , Bobek Vladimir , Suetsugu Atsushi , Zhang Nan , Hoffman Robert M. 
Published: March 2020

e21051 Background: Knowledge of the metastatic potential of circulating tumor cells would be useful for cancer prognosis and also be a rationale for targeting metastatic CTCs for therapy. Methods: Using immunomagnetic beads, CTCs were rapidly isolated from the circulation of mice orthotopically implanted with human PC-3 prostate cancer cells stably expressing green fluorescent protein (GFP). The PC-3–GFP CTCs were then expanded in culture in parallel with the parental PC-3–GFP cell line. Both cell types were then inoculated onto the chorioallentoic membrane (CAM) of chick embryos. Eight days later, embryos were harvested and the brains were processed for frozen sections. The IV-100 intravital laser scanning microscope enabled rapid identification of fluorescent metastatic foci within the chick embryonic brain. Results: Inoculation of embryos with PC-3–GFP CTCs resulted in a 3 to 10-fold increase in brain metastasis when compared to those with the parental PC-3–GFP cells (p<0.05 in all animals). Thus, PC-3–GFP CTCs have increased metastatic potential compared to their parental counterparts. Conclusions: The chick embryo represents a rapid, sensitive, imageable assay of metastatic potential for CTCs. The chick embryo assay has future clinical application for individualizing patient therapy based on the metastatic profile of their CTCs.
Effect of orally administered S-1 on circulating endothelial cells in patients with metastatic breast cancer.
Authors: Tsuji Wakako , Ishiguro Hiroshi , Ueno Takayuki , Toi Masakazu 
Published: March 2020

e21052 Background: S-1 is an oral cytotoxic preparation combining tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate at a molar ratio of 1:0.4:1, respectively. Tegafur is metabolized into 5-fluorouracil (5-FU), γ-butyrolactone (GBL), and γ-hydroxybutyric acid (GHB). GBL and GHB are known to suppress VEGF-mediated angiogenic activity. Circulating endothelial cells (CECs) have been suggested to be useful for predicting response to anti-angiogenic agents. We evaluated the effects of S-1 on CEC counts in patients with metastatic breast cancer. Methods: Patients with metastatic breast cancer received S-1 orally in 28-day cycles. The dose of S-1 was 80-120 mg/day depending on body surface area. Cycles were repeated every 42 days. CEC counts were measured with the CellSearch system (Veridex, LLC Co. Ltd., NJ) on days 1 (before the 1st cycle of S-1), 15, 29, 43 (before the 2nd cycle of S-1), and 85 (before the 3rd cycle of S-1). Plasma GBL and 5-FU levels were measured by a gas chromatographic-mass spectrometric method at one point each on days 1 (before the 1st cycle of S-1), 15 (1 hour after S-1 administration), 43 (before the 2nd cycle of S-1), and 57 (1 hour after S-1 administration). VEGF levels on days 1, 15, 43, and 57 were measured by an enzyme-linked immunosorbent assay. Results: A total of 18 patients were enrolled. Plasma GBL levels on days 15 and 57 were 42.0 ± 16.2 ng/mL and 43.2 ± 10.5 ng/mL, respectively. Both levels exceeded 25.8 ng/mL, the previously reported (Angiogenesis 2001). Both CEC and CD34+CEC levels significantly decreased on day 15, and low levels were maintained low until day 85. Plasma levels of VEGF also decreased similarly, but not significantly. Conclusions: The results of this exploratory study suggest that S-1 not only has cytotoxic effects on tumor tissue, but also anti-angiogenic activity in patients with metastatic breast cancer.