bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metronomic chemotherapy following the maximum tolerated dose as a multitarget antitumor therapy affecting angiogenesis, tumor dissemination, and cancer stem cells.
Authors: Vives Marta , Ginestà Mireia M. , Gracova Kristina , Graupera Mariona , Casanovas Oriol , Capella Gabriel , Serrano Teresa , Vinyals Francesc , Saez Berta Laquente 
Published: March 2020

e22057 Background: Metronomic chemotherapy has been suggested as a maintenance administration strategy after the Maximum Tolerated Dose (MTD) treatment in a multi-targeted chemo-switch schedule (C-S). We report the effectiveness of this chemo-switch schedule in mice models of human pancreatic and ovarian cancer. Methods: In pancreas cancer models, Gemcitabine (G) was administered on four different schedules: metronomic (METG), Maximum Tolerated Dose (MTDG), chemo-switch schedule (C-SG, MTDG dosing followed by the METG) and anti-angiogenic (MTDG followed by the administration of monoclonal anti-VEGF receptor antibody DC101). In ovarian cancer model, animals were treated following a Cyclophosphamide chemo-switch schedule (C-S CTX). Results: In all these models C-S schedule had the most favorable effect, reaching at least 80% of tumor growth inhibition in absence of increased toxicity. Moreover, in the pancreas cancer model while peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis and its effect on tumor growth was similar to obtained by the MTD followed by anti-angiogenic DC101 treatment. At the molecular level, C-S treatment combined an increase in thrombospondin-1 expression with a decrease in number of CD133+ cancer cells and triple positive CD133+/CD44+/CD24+ cancer stem cells. Conclusions: These findings provide confirmation that the chemo-switch schedule is a challenging clinical strategy with demonstrated inhibitory effects on tumor dissemination, angiogenesis and cancer stem cells.
Discordance of the ER- and HER2-status on disseminated tumor cells (DTCs) compared to the primary tumor (PT) in patients with early breast cancer (BC).
Authors: Jaeger Bernadette Anna Sophia , Finkenzeller Charlotte , Bock Carolin , Majunke Leonie , Jueckstock Julia Kathrin , Andergassen Ulrich , Neugebauer Julia Katharina , Pestka Aurelia , Friedl Thomas W. P. , Jeschke Udo , Janni Wolfgang , Doisneau-Sixou Sophie F , Rack Brigitte Kathrin 
Published: March 2020

e22059 Background: The goal of this study was to evaluate both ER- and HER2-status on DTCs in the bone marrow of patients with early BC and to compare these with the corresponding PT. In case of discordant expression, DTCs might help in properly selecting targeted therapy according to their phenotype. Methods: Bone marrow (BM) samples were obtained from early BC patients at the time of first breast surgery (years 2006 to 2009). Two cytospins with 106 BM cells were prepared after Ficoll enrichment for mononuclear cells. We were able to determine the presence of DTCs (cytokeratin (CK)+cells) in a total of 58 patients. Simultaneously ER- and HER2-expressions were analyzed by immunocytochemistry using a triple fluorescence staining method. Briefly, antibodies (AB) directed against human ER (secondly labeled with Cy3, red), HER2 (DyLight488, blue) and CK (Coumarin-AMCA, green) were used. The manual analysis was conducted using a computerized fluorescence microscope (Axioskop, Zeiss, Germany). Criteria for CK-positivity and HER2-overexpression were the ring-like appearance of the respective membrane-staining and for ER-expression a nuclear staining. Data on ER- and HER2-status of the PT were available for all 58 and 54 of the patients respectively. Results: The median number of DTCs detected was 12 (range 1-95; total number of DTCs 1132). 41 (71%) of the patients had at least one ER+ DTC, 25 (43%) at least one HER2+ DTC, 15 (26%) at least one ER+/HER2+ DTC and 13 (22%) had DTCs neither expressing ER nor HER2. The concordance rate between ER-status on DTCs and PT was 74%. 6 (43%) patients with ER- PT had ER+ DTCs. The concordance rate between HER2-status on DTCs and PT was 52% and 22 (46%) patients with HER2- PT had HER2+DTCs. Seven out of 10 patients with a triple-negative PT had at least one DTC positive for ER, HER2, or both. Conclusions: Our study confirms that the ER- and/or HER2-status on DTCs might differ compared to the PT. This discordance, which we demonstrated at the protein level, could be especially important for patients with a triple-negative PT and ER+ or HER2+ DTCs, since they might respond favorably to an endocrine or HER2-targeted therapy.
Epidermal growth factor mutation in non-small cell lung cancer: Venezuelan experience.
Authors: Oblitas Alca George , Fuentes Maria Belen , Rodriguez Juan Jose Jose , Garcia Cristina , Perez Maria Angelina , Kubicek Karen , Nunez Patricia , Pichelbauer Ernestina 
Published: March 2020

e22060 Background: Lung cancer represents the most common cause of death related to cancer worldwide. The current treatment strategy includes the determinations of the EGFR somatic mutations. Currently in Venezuela the frequency and the type of EGFR mutation in NSCLC patients is unknown and due to its importance in the decision of treatment, it was decided to execute this study with the objective of knowing our population’s characteristics with respect to the stage and mutational type of EGFR. Methods: In the period between November of 2010 until March of 2012, the samples of 395 patients with NSCLC diagnostic all over the country were obtained, these samples were evaluated to determine the EGFR mutation, confidence intervals of 95% were calculated based on the binomial distribution. Results: From the total of 395 patients, 80 presented an inadequate sample, 19 had no registry, 296 patients remained for the analysis. It was obtained an EGFR mutation rate of 11.5%, that was more common seen in male gender (56%), younger than 65 years (66%), ex smokers (59%), with Adenocarcinoma histology (97%). About the mutation type of the EGFR, the specific mutation of the exon 21 was found in 59% of the positive cases, and deletion of exon 19 in 38%. Conclusions: The EGFR mutation is present within the Venezuelan population and shows a particular regional demographic behavior.
The effect of cholesterol on cancer growth and metastasis: Experimental study with LDL receptor knockout mice.
Authors: Pu Daniel , Cui Yuqi , Liu Zhenzhen , Parthasarathy Sampath , Bai Xuefeng , Liu Zhengou 
Published: March 2020

e22071 Background: Cholesterol is an essential component for normal cell growth. However, epidemiological studies show cholesterol levels may be associated with cancer incidence. The Multiple Risk Factor Intervention Trial reported a significant inverse relationship between cholesterol levels and lung cancer. The effects of cholesterol on cancer growth and metastasis have not been established. The aim of the present study was to determine if cholesterol alters cancer growth or metastasis. Methods: The study used 48 wild-type mice and 18 LDL receptor knockout mice (LDLR-/-). Mice were randomized into 3 groups: Group I (wild-type mice fed normal chow, n=23); Group II (wild-type mice fed high lipid chow, n=25); Group III (LDLR-/- mice fed high lipid chow, n=18). Human melanoma cells were injected subcutaneously for the assessment of growth and intravenously for metastasis. Mice were followed for 4 weeks. At the end of the study, mice were weighed and autopsy was performed. Melanoma weight, metastasis, and blood cholesterol levels were evaluated. Data was analyzed using One-way ANOVA and Chi-square. Results: LDL-cholesterol level was significantly higher in Group III than Group I (1103±472 vs.28±6; p<0.01). There was no significant difference in melanoma weight (2.74g ±1.77, 2.98g±1.98 vs. 2.18g±1.59, P=0.56) among the three subcutaneous injection groups. Lung metastasis was observed in all intravenous injection groups (11/11 vs. 10/10 vs. 8/8). There was no difference in melanoma weight or metastasis between male and female mice (P>0.05). There was no difference in net weight gain among the subcutaneous injection groups (4.12g±2.50 vs. 2.64g±2.79 vs. 3.66g±1.96, P=0.30). However, among the intravenous injection groups, weight gain was observed in Group II (2.78g±2.67) and Group III (2.36g±1.73) and weight loss in Group I (-0.32g±1.34, P<0.003). Conclusions: Cholesterol has no effect on melanoma growth or metastasis in mice. A high cholesterol diet may reduce weight loss in animals with metastatic melanoma. Further study is warranted to determine whether similar results exist in other types of cancers and to evaluate a possible beneficial effect of high lipid diets on patients with metastatic cancers.
Creating clinical target validation groups via quality assured transfer of robust clinical pharmacodynamic (PD) assays from the NCI: Clinical implementation of a PAR immunoassay in tumor biopsies.
Authors: Parchment Ralph E. , Kinders Robert J. , Ji Jiuping Jay , Srivastava Apurva K. , Ferry-Galow Katherine V. , Tomaszewski Joseph E. , Doroshow James H. 
Published: March 2020

e22080 Background: Early phase clinical trials of investigational agents benefit from laboratory assays that quantify intended mechanism of action on molecular target (1° PD effects), desired changes in mechanistic biomarkers (2° PD effects), and 3° PD effects on cell survival. Robust PD assay results are valuable for informing go/no‐go decisions about continued development of new agents and for identifying combinations of targeted agents that cover the multiple molecular defects underlying many malignancies. Methods: Readying PD assays for clinical use involves validating analytical performance, identifying and qualifying critical reagents, demonstrating fit‐for‐purpose for the clinical protocol, and finalizing companion SOPs specifying specimen handling and processing. Because clinical PD questions often demand assay performance that meets or even exceeds clinical diagnostic assay standards, but key assay reagents are usually R and D‐rather than GMP‐grade, stringent reagent Quality Control is critical for preventing assay failures due to lot-to-lot variability. Results: The poly(ADP-ribose) (PAR) Immunoassay was the first qualified assay developed by NCI for implementation in early phase clinical trials. Development of stringent production and internal Quality Control specifications for accepting/rejecting new lots of critical reagents and a defined Quality Assurance Plan allowed a network of users to achieve consistent results and quality using R&D-grade source materials. Conclusions: The NCI’s Division of Cancer Treatment and Diagnosis is developing a clinical PD assay portfolio capable of quantifying 1°, 2°, and 3° PD effects. Proven clinical assays are formally transferred from the NCI to requesting sites in academia and industry via laboratory‐based certification and training, centralized access to SOPs, assistance with assay transfer, and participation in the assay’s Quality Assurance Plan. Funded by NCI Contract No HHSN261200800001E.
Routine molecular profiling of solid tumors in a community cancer center's genomic pathology laboratory.
Authors: Gunn Shelly , Reveles Xavier , Smith Lon S. , Rodriguez Gladys Isabel , Patnaik Amita , Beeram Muralidhar , Papadopoulos Kyriakos P. , Rasco Drew Warren , Tolcher Anthony W. 
Published: March 2020

e22088 Background: Selection of targeted therapeutics for solid tumors depends upon detection of actionable genomic alterations in archival tissue. High-throughput molecular profiling at the community level would allow local pathologists to participate with oncologists in the delivery of personalized cancer medicine. Methods: Between March and December 2012, molecular profiling was performed on FFPE tumor tissue sent to Oncopath (our in-house CAP/CLIA genomic pathology laboratory) from 330 patients with diverse types of metastatic and non-resectable solid tumors. Tumor-targeted DNA was analyzed for genome-wide copy number alterations by array-based comparative hybridization (CGH), and mutation analysis (MA) using multiplex PCR with mass spectrometric genotyping (mass spec), or single gene allele-specific PCR (PCR). Results for 96 actionable genes analyzed by CGH, and MA were correlated with clinically or pre-clinically available targeted therapeutics. Actionable biomarkers for FDA approved therapies (e.g. BRAF V600E/vemurafenib) and prospective biomarkers for Phase I/II trials (e.g. CCND1 gene amplifications and CDKN2A gene deletions/CDK inhibitors) were reported for each patient. Results: Of 330 cases, 216 had at least one and as high as seven actionable biomarkers. The remaining 114 cases had either no tumor specific changes (n=17) or non-actionable oncogenic changes (n=97). The most commonly analyzed tumors were breast, brain, lung, colorectal, pancreatic, head & neck, and ovarian. Rare tumor types with positive biomarkers included an HRAS Q61R positive adenoid cystic carcinoma and a BRAF V600E positive pleomorphic xanthroastrocyoma. Tumor DNA was stored for 100% of patients and all cases were reported synoptically listing actionable biomarkers with therapeutic recommendations. Conclusions: Molecular profiling in a community cancer center facilitates biomarker detection for rational direction of patients to targeted therapeutics. New technologies for detection of actionable biomarkers will continue to be implemented in our center to improve the likelihood of effective treatment for each individual patient’s tumor.
Association of myeloid-derived suppressor cells (MDSCs) in peripheral blood with characteristics in breast cancer patients.
Authors: Shen Peng , Wang Aijuan , Ke Wei , He Mengye , Yu Lanfang , Huang Sui 
Published: March 2020

e22094 Background: The immune therapy of human cancer is a promising therapeutic approach. Myeloid-derived suppressor cells (MDSCs) have been confirmed as an indispensable component of immune system and associated with tumor induced immune suppression. Thus, MDSCs play an important role in immune therapy. Although a lot of research work has been done, currently there exists limited data about MDSCs status in cancer patients. The aim of this study was to determine whether MDSCs levels in peripheral blood were different in healthy volunteers, benign breast tumor patients and breast cancer patients, and to investigate the relation between MDSCs and several characteristics in breast cancer patients. Methods: Peripheral blood cells (PBC) were collected from 36 normal healthy volunteers, 52 patients with breast cancer and 62 patients with benign breast tumor. Peripheral blood samples of breast cancer patients were obtained before treatment. Circulating MDSCs (identified as Lin-/Lo HLA-DR-CD33+) were measured by flow cytometry. Statistical methods included two sample t tests and one way ANOVA. Results: The percentage of MDSCs was higher in breast cancer than benign breast tumor patients and healthy volunteers (2.017% vs 1.578% vs1.594%; p=0.0002), and the stage III/IV breast cancer patients had more MDSCs accumulation than those in stage I/II (2.92% vs 2.155%; P=0.0806). The levels of MDSCs in peripheral blood showed a significant correlation with HER-2/neu expression in breast cancer patients, but had no correlation with incidence age, ER status, PR status and P53 expression respectively. The percentage of MDSCs was lower in HER-2/neu over expression breast cancer patients than HER-2/neu negative patients (1.715% vs 2.882%, GP=0.0012). Conclusions: MDSCs seemed to have positive correlation with clinical stage and negative correlation with HER-2/neu expression in breast cancer patients . Further research will contribute to the better understanding of the connection between MDSCs and breast cancer, to develop better approaches to breast cancer therapy.
A combined EpCAM and MCAM circulating tumor cell (CTC) CellSearch enrichment to improve CTC capture rate in stage II/III breast cancer: A Dutch Breast Cancer Trialists' Group (BOOG) side study.
Authors: Onstenk Wendy , Kraan Jaco , Charehbili Ayoub , Mostert Bianca , Smit Vincent T. H. B. M. , Kroep Judith R. , Nortier J. W. R. , Liefers Gerrit-Jan , van de Ven Saskia , Heijns Joan Barbara , Kessels Lonneke , Van Laarhoven Hanneke W. M. , Bos Monique M.E.M. , Van De Velde Cornelis J. H. , Gratama Jan-Willem , Sieuwerts Anieta M. , Martens John W. M. , Foekens John A. , Sleijfer Stefan 
Published: March 2020

e22106 Background: Using the CellSearch System (Veridex, USA), ≥1 CTC/7.5 mL of peripheral blood is found in ~20% of primary breast cancer (BC) patients. However, epithelial cell adhesion molecule (EpCAM)-negative CTCs may be missed. We previously showed that a subset of BC cell lines lacks EpCAM, but does express melanoma cell adhesion molecule (MCAM) and that MCAM-positive CTCs (M-CTCs) do occur in metastatic breast cancer patients. In a side-study of the NEOZOTAC trial, a randomized study comparing neoadjuvant chemotherapy (NAC) with or without zoledronic acid in stage II/III BC, we investigated whether combined enrichment with EpCAM and MCAM increases the CTC detection rate. Besides, we hypothesized that CTC counts would correlate with pathological complete response (pCR) to NAC. Additionally, as exploratory study, circulated endothelial cells (CECs) were measured. Methods: At baseline and after the 1st chemotherapy cycle, blood was drawn from all patients in the NEOZOTAC trial who gave additional informed consent. The CellSearch System was used to count EpCAM-positive CTCs (E-CTCs) and M-CTCs. For the latter, the anti-EpCAM-ferrofluid was replaced by an anti-MCAM-ferrofluid (both Veridex). CECs were measured using flow cytometry. Results: At baseline, blood was received from 73 patients; ≥1 E-CTCs and M-CTCs were detected in 14/73 (19%, median 1) and 8/68 (12%, median 1), respectively. Combining both counts, ≥1 CTCs were detected in 17/68 (25%) of patients (p=0.01). After 1 chemotherapy cycle, E-CTCs, M-CTCs and overall CTCs were detected in 9/47 (19%), 7/45 (16%), and 13/44 (30%; p<0.01) patients. Median CEC count was 43 at baseline and 142 after cycle 1 (p<0.001). No differences in CTC and CEC count were found between the treatment arms. Baseline CTC counts, nor changes in counts, were associated with pCR. Conclusions: Combined enrichment of CTCs with EpCAM and MCAM significantly increased CTC detection rates in stage II/III BC with about 10%. CTC counts were not associated with pCR to NAC. Associations with disease free survival will follow when available.
Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors.
Authors: Drevs Joachim , D'Urso Susanne , Dayton Martin , Martinez Lukas , Mueller-Huebenthal Jonas , Kamijo Izumi , Kreutz Werner 
Published: March 2020

e22114 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of > 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of > 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of > 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.
Molecular analysis in breast cancer subtypes and correlation with pathologic complete response (pCR) to neoadjuvant chemotherapy.
Authors: Gonzalez Cao Maria , Costa Carlota , Molina-Vila Miguel Angel , Cusido Maria Teresa , Viteri Ramirez Santiago , Baulies Sonia , Martinez-Bueno Alejandro , Fabregas Rafael , Tresserra Francesc , Sansano Irene , Ara Carmen , Amselen David , Ubeda Belen , Simo-Perdigo Marc , Gasco Amaya , Rodriguez Ignacio , Rosell Rafael 
Published: March 2020

e22119 Background: Although it is know that pCR following neoadjuvant chemotherapy is more frequent in some subtypes of breast cancer such as Triple Negative (TN) or erb2 tumors, the predictive role of gene expression and mutation status is not well defined in this setting. Methods: We analyzed samples from 41 patients (p) prospectively treated with neoadjuvant chemotherapy (sequential AC followed by weekly TXL, or inverse sequence, plus trastuzumab for erb2 positive p). Pathologic response (PR) was classified according to Miller-Payne and RCB criteria. Radiologic evaluation was performed by ultrasonography, dynamic MR and PET-TAC after each chemotherapy sequence. We performed expression analysis of AXL, BRCA1, RAP80, BIM, EZH2, ROR1, FGFR1, PTPN12, YAP, GAS6, beta-TRCP, HIF1 alpha and ZNF217 by RT-PCR, and mutational status of p53 and PI3K genes in pretreatment biopsies. Statistical analysis was performed using Mann-Whitney U and Pearson’s chi-squared tests. Results: pCR was detected in 5 p (3TN, 2 erb2) of 25 p (9 luminal A, 5 luminal B, 6 erb2 and 5 TN) evaluated for PR at time of submitting this abstract. TN tumors had lower levels of RAP80 (p=.0013), PTPN12 (p=.003), beta TRCP (p=.001), ZNF217 (p=.014) and YAP (p=.097). Luminal B tumors had low levels of YAP and the highest levels of FGFR1 (p=.09) and ZNF217 (p=.014). Luminal A tumors had high levels of beta-TRCP (p=.003). We found no differences in BRCA1, AXL, BIM, EZH2, ROR1, GAS6 and HIF1 levels by breast cancer subtype. P with low levels of FGFR1 (p=.087), HIF1alpha (p=.07) or EZH2 (p=.005) had higher probability of pCR. No pCR was observed in p with higher levels of AXL, EZH2, RAP80, GAS6, beta TRCP, HIF alpha. Four p had p53 mutations (1 luminal B, 1 erb2 and 2 TN) and 4 p had PI3K mutations (2 luminal A, 1 erb2, 1 luminal B). There was no correlation between p53 status and PR. P with PI3K mutations did not achieve pCR vs 46% of p with wild type PI3K (p=.23). Conclusions: Gene expression profile varies by breast cancer subtype. Chemosensitivity could be higher in tumors with lower levels of FGFR1, HIF1alpha or EZH2. Further results will be presented.