bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel tumor markers in non-small cell lung cancer detected both in serology and tissue.
Authors: Radhi Saba , Alalawi Raed , Mirandola Leonardo , Yu Yuefei , Pandey Apurva , D'Cunha Ruth , Saadeh Charles , Nguyen Diane Duyen Thuy , Hardwicke Fred L. , D'Cunha Nicholas C. , Tijani Lukman Adeoju , Jenkins Marjorie , Jumper Cynthia A. , Chiriva-Internati Maurizio , Cobos Everardo 
Published: March 2020

e21105 Background: Cancer testis antigens (CTA) are a class of tumor associated antigens, showing a restricted expression in cancer, a strong immunogenicity and weak expression or absence in normal tissues. CTA are a growing family of proteins involved in signal transduction control. Sp17/AKAP4/PTTG1 have been previously investigated, showing promising results as a target antigens. Our aim was to investigate the expression of Sp17/AKAP4/PTTG1 in lung cancer patients. Methods: We analyzed 2 lung cancer cell lines, one normal bronchus cell line, a panel of normal tissues and patient’s cells by RT-PCR, flow-cytometry, immunocytochemistry (ICC), and immunofluorescence (IF). CTA immunogenicity was investigated by measuring circulating specific antibodies in the sera of lung cancer patients. PCR was performed by 35 amplification cycles. RNA integrity in each sample was checked by amplification of ß-actin. We studied the pattern of expression in patients with NSCLC according to histology, gender, and age. Results: Specimens from 11 patients were examined.CTA, Sp17, AKAP-4 and PTTG-1 are aberrantly expressed in lung cancer cell lines and primary cells from patients by RT-PCR, immunocytochemistry, and flow cytometry. ELISA analyses show the presence of circulating CTA-specific antibodies in the sera of lung cancer patients, indicating the immunogenicity of Sp17, AKAP-4 and PTTG-1. The mean age of patients was 60 years(range 57-76). Fifty eight percent were males(N=7). Seventy two percent (n=8) had adenocarcinoma. Six patients were stage IV at diagnosis. There was no difference in the pattern of expression between gender, stage or histology. Conclusions: We showed that CTA, Sp17, AKAP-4 and PTTG-1 can be detected in both sera and tissue of patients with NSCLC. They are potential therapeutic targets for immunotherapies. These may me useful in determining response to treatment as well as asses possible recurrence.
Evaluation of the pattern of SOX2 expression in non-small cell lung cancer (NSCLC) and correlation with clinicopathologic (CP) features and prognosis.
Authors: Velcheti Vamsidhar , Cheng Huan , Yao Xiaopan , Deng Yanhong , Gettinger Scott N. , Rimm David 
Published: March 2020

e21106 Background: SOX2 is an embryonic stem cell transcription factor that plays a crucial role in differentiation and maintaining pluripotency. We examine the pattern of SOX2 expression and assess correlation with CP features in NSCLC. Methods: Using the AQUA method of automated quantitative immunofluorescence we measured SOX2 expression in two cohorts (in a tissue microarray format), from Yale New Haven Hospital (YTMA 79) and an independent cohort from Patras University Hospital in Greece (YTMA 140) (196 and 342 cases, respectively). YTMA 140 had high percentage of Squamous cell carcinoma (SCC) (48.8%) as opposed to 17.9% in YTMA 79. There were more stage III & IV pts in YTMA 140 (41.3%) compared to YTMA79 (30.6%). 88% of pts in the YTMA 140 were male compared to 52.5% in YTMA79. Survival analysis was done using Kaplan-Meier analysis with log-rank test. The associations between SOX2 expression level and CP features were evaluated by using non-parametric Kruskal-Wallis test. Results: In both cohorts, we found significantly higher SOX2 expression in SCC compared to adenocarcinoma. There was no correlation with gender or stage. Using the threshold of specific signal detection as the cut point, we divided the cohorts into expressers and non-expressers. YTMA 140 cohort which is enriched in SCC showed that 28/161(17.3%) pts with SCC were SOX2 non-expressers. Pts who were SOX2 non-expressers had a worse median overall survival (15 months) compared to pts who were SOX2 expressers (23.5 months) (p=0.015). Conclusions: Our data reveals that pts who have SCC have significantly higher expression of SOX2 and higher SOX2 expression correlates with better outcome. Further studies to define the molecular characteristics of SCC may elucidate more effective markers and effective classification for NSCLC.
Primary breast cancer tryptase expression as novel molecular drug target.
Authors: Ranieri Girolamo , Ammendola Michele , Brandi Mario , Misino Andrea , Goffredo Veronica , Patruno Rosa , Di Lecce Valentina , Gadaleta Caldarola Gennaro , De Sarro Giovambattista , Sacco Rosario , Gadaleta Cosmo Damiano 
Published: March 2020

e21113 Background: Tryptase, a serine protease stored and released from mast cells granules has been identified as a new non-classical angiogenetic factor. Mast cells can release tryptase following c-Kit receptor activation. We have evaluated the correlations among the number of MCs positive to tryptase (MCDPT), the number of c-Kit receptor expressing cells (C-KREC) and microvascular density (MVD) in a series of 88 primary T1-3, N0-2 M0 female breast cancer by means of immunohistochemistry and image analysis methods. Methods: Six-micrometers thick serial sections of formalin-fixed and paraffin-embedded bioptic tumor samples were microwaved at 500 W for 10 min. and treated with a 3% hydrogen peroxide solution. Sections were incubated with primary antibodies: anti-tryptase (AA1; Dako, Glostrup, Denmark), anti-c-Kit receptor (A4502;Dako, Glostrup, Denmark) and anti-CD34 (QB-END 10; Bio-Optica Milan, Italy). In serial sections MVD, MCDPT and C-KREC were counted by means of image analysis at x400. Results: Data demonstrated a significantly (r= ranging from 0.71 to 0.91; p: ranging from 0.001 to 0.003 by Pearson’s analysis respectively) correlation between MVD, MCDPT and C-KREC to each other. Conclusions: Published in vitro data suggest that tryptase induce angiogenesis in vascular endothelial cells and breast cancer cells lines. According to these data we shown that MVD, MCDPT and C-KREC paralleled to each other suggesting a role in in vivo breast cancer angiogenesis. In this context several tryptase inhibitors such as gabexate mesilate or nafamostat mesilate might be evaluated in clinical trials as a new antiangiogenetic approach.
Frequency of EGFR mutations in Greek non-small-cell lung cancer (NSCLC) patients.
Authors: Murray Samuel , Papadopoulou Eirini , Nasioulas George 
Published: March 2020

e21141 Background: NSCLC patients harboring activating somatic mutations within the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) significantly benefit from EGFR targeted therapy. Treatment with the recently approved EGFR inhibitor IRESSA (gefitinib) leads to improved response and survival outcomes, therefore screening for EGFR mutations has entered routine clinical practice. Several clinico-pathological factors correlate with these mutations including gender, smoking history, and histology. The frequency of EGFR mutations is also ethnicity-dependent, wherein the incidence in Asian populations is ~30%, while in Caucasians (Whites) it is lower, ~ 15%. However, limited data is available on intra-ethnic differences throughout Europe. Aim: The aim of this study was to determine the frequency and spectrum of EGFR mutations in an unselected group of Greek NSCLC patients and investigate technical aspects of analysis. Methods: We set up High Resolution Melting Analysis (HRMA) assays to identify mutations in exons 18-21 of the EGFR gene and validated their analytical sensitivity by making serial dilutions of samples with known mutations and tumor cell content (TCC). A total of 698 NSCLC patients were screened with HRMA for somatic EGFR mutations in exons 18-21 and mutation status was verified by bi-directional sequencing. Pathological review was obtained for all samples and macro-dissection was used to ensure a %TCC of >75% in all possible cases. Results: The sensitivity of our HRM assays was found to be ≤1.5% Using HRMA and bi-directional sequencing a frequency of 19.05% was obtained; 105 x exon 19, 21 x exon 21, 6 x exon 20 and 1 x exon 18 . Conclusions: Applying a very sensitive mutation detection technique in a large cohort of unselected Greek NSCLC patients in routine diagnostic practice, we obtained an overall mutation frequency of 19.05%. This mutation frequency is similar to that found by the SLADB and EURTAC studies in European populations. Differences in sensitivity between techniques suggest that more than one technique should be advised in routine diagnostic practice.
A review of chromosome 3q abnormalities in lung cancer.
Authors: Subramonia-Iyer Subramony , Hrinczenko Borys 
Published: March 2020

e21154 Background: With the refinement of genetic analytic techniques more detailed and precise information about 3q abnormalities has become available. The aim of this study was to review and summarize the literature about chromosome 3q in the pathogenesis, classification, treatment and prognosis of lung cancer. Methods: A MEDLINE search was conducted with the terms “lung cancer” and “3q”. Papers that described 3q abnormalities in the context of lung cancer were included in this review. Results: From 1990-2011, 61 papers were identified that described chromosome 3q changes in lung cancer. Initial studies showed 3q amplification in premalignant lesions, bronchial dysplasia, NSCLC and SCLC tumor tissue. Similar 3q amplifications were found in lung cancer cell lines at the 3q26-q28 region, including the gene for telomerase (hTR). Amplification of 3q segments were more prevalent in squamous (40 -100%) than in adenocarcinoma (6 - 25%) and in smokers than in non-smokers. However, malignant cells from pleural effusions of adenocarcinoma showed 3q gains in nearly 40% of cases. Genes located on 3q such as RAP2B, CLDN1 and TBL1XR1 were overexpressed in squamous carcinoma. High gain levels were also found at PIK3CA, EVI1 (3q26.2), LPP (3q27-28) and FHF-1 (3q28) gene loci. Also, 3q gains were associated with EGFR mutations in squamous carcinoma and TP53 mutations in adenocarcinoma. Prognostic importance of several chromosomal changes in lung cancer has also been examined. In one study, overexpression of eIF5A-2, located on 3q, was found to correlate with gene amplification, increased cell proliferation, local invasion, advanced T stage, and poor prognosis in stage I NSCLC [He, Int J Cancer, 2011]. Conclusions: Genetic abnormalities and changes in chromosome 3q have been increasingly well characterized with specific genes identified. Differential expression in various histological types of NSCLC indicates that these genes may contribute to the pathogenetic pathway in squamous carcinoma, and also in locally advanced adenocarcinoma with pleural effusions. These genes have also been shown to be prognostically important. With these promising results, further identification of specific 3q gene products may lead to the development of novel therapeutic targets in lung cancer.
Contribution of platelets to tumor aggressivity.
Authors: Delage Judith , Li Hong , Lu He , Cazin Lionel , Soria Jeannette , Dupuy Evelyne , Drouet Ludovic , Vannier Jean-Pierre , Varin Rémi , Soria Claudine 
Published: March 2020

e21156 Background: The interaction between cancer and coagulation process has been shown since many years. The aim of our study is to understand the mechanisms implicated and to propose new therapeutic approaches. Methods: Two breast cancer cell lines were used: a very aggressive (MDA-MB231) and a much less aggressive (MCF-7). Platelet aggregation tests were done with washed platelets, normal or fibrin removed plasma and cancer cells (20 to 2.105 cells/ml). Procoagulant activity of cancer cells was studied. Aspirin, Apyrase (ADPase), a direct thrombin inhibitor (Hirudin), two Xa inhibitors (Fondaparinux, Rivaroxaban) were the inhibitors tested. Interaction between platelets and cancer cells was visualized by confocal microscopy. Angiogenic effect of supernatants from platelets-cancer cells co-incubation was investigated. Results: The data obtained show that a platelet aggregation is induced by cancer cells in the presence of a small amount of plasma. This aggregation depends on both the type and number of cancer cells. Aggressive MDA-MB231 cells have a more potent pro-aggregating activity than MCF-7. This aggregation appears to be due to thrombin generation since it is inhibited by Hirudin. Rivaroxaban, a direct inhibitor of factor Xa, inhibits platelets aggregation but not Fondaparinux, an indirect anti Xa inhibitor which binds to Antithrombin III. Aspirin and Apyrase have no effect. Moreover, the procoagulant activity of cancer cells with plasma is inhibited by Hirudin and Rivaroxaban but not by Fondaparinux. This suggests that the Fondaparinux-Antithrombin III complex cannot access to cell membrane-bound factor Xa. It may be due to its steric hindrance since thromboplastin induced coagulation is inhibited by Rivaroxaban but not by Fondaparinux. The confocal microscopic study shows that platelets protect tumor cells from immune attack via the formation from a protective envelope around cancer cells. Angiogenesis assays show that activation of platelets by cancer cells releases angiogenesis stimulating factors and cytokines. Conclusions: The present work confirms the crucial role of platelets in cancer aggressiveness and reveals that Rivaroxaban or Thrombin inhibitors could be efficient drugs to reduce cancer progression, metastasis and thrombosis.
Integrated laboratory networks for a successful biomarker implementation strategy in personalized medicine.
Authors: Paz Maria fe , Ferreiro Jose Luis , Keeling Peter 
Published: March 2020

e21158 Background: Much work has been done to ensure that biomarkers research and the development of targeted therapies in Oncology can be translated into a better stratification of patients. However, when it comes to the implementation of those biomarkers into the clinical setting, laboratories are not commonly consider an essential stakeholder. Unfortunately, the laboratories are often the forgotten third arm of a successful foundation in personalized medicine (PM), for molecular diagnostics in oncology. In order to truly enhance the power of companion diagnostics, and to better meet healthcare demands and finally, patient needs, superior integrated laboratory services are crucial. This presentation will provide a brief introduction from Labceutics highlighting the need for highest quality laboratory networks across Europe. In addition it would feature results of a Delphi survey of leading EU laboratories on the gaps and shortfalls they face in implementing companion diagnostics Methods: Delphi survey study conducted over a representative sample of the +120 partners in the Labceutics European Laboratory network. Statistical analysis was performed with SPSS software. Results: this research reveals that that fewer than 10% of these laboratories had been contacted directly by pharmaceutical companies to discuss the future implementation issues they may face in introducing companion diagnostics in their Lab. Additionally, the study confirmed that 25% of the laboratories surveyed, preferred to begin their testing service of a novel diagnostics with an IVD kit purchased from a diagnostic company. On the other hand, 77% either preferred to develop their own in house method or consider the business case, since so many of the new diagnostics have very low volumes in the initial 3 to 5 years. Conclusions: this exhaustive will provide the audience with insights into the main issues about best practices for laboratories to ensure appropriate implementation of testing services. It will reveal as well, the importance and sequence of "early prelaunch" engagement with a laboratory network to accelerate post launch diffusion of testing.
Disruption of protocadherin function as an indicator of cancer progression.
Authors: Shima James , Delaney Joseph , Umesh Anita , Park Jenny , Wall Gregory , Su Qiaojuan , Shekar Mamatha , Kupershmidt Ilya 
Published: March 2020

e21159 Background: Protocadherins (PCDH) are a large family of calcium-dependent cell–cell adhesion molecules that are involved in tissue morphogenesis, in particular the development of the central nervous system. Recently, alteration of PCDH alpha/beta/gamma locus genes have been implicated in a number of oncogenic processes: hypermethylation of the PCDH locus in Wilms’ tumor progression and metastasis, differential expression of some PCDH genes between bone and brain metastases in breast cancer patients, and epigenetic silencing of PCDH gamma A11 in astrocytoma invasion of the adjacent parenchyma. Assessment of PCDH function could help guide treatment decisions by aiding in the identification of cancer patients who are more likely to develop metastases. Methods: Identification of altered PCDH locus genes in cancer patient samples was performed using the NextBio platform which incorporates curated public genomic data from numerous sources, including TCGA, GEO, COSMIC, and others. Correlation of numerous data types was used to identify deleterious mutations, altered RNA expression, and copy number changes that were indicative of metastasis or a more advanced disease state. Results: A nearly 3-fold increase in the frequency of potentially detrimental somatic mutations in the PCDH gamma locus was observed in breast and ovarian cancer patients with extensive lymph node metastases (N3) compared to patients with a lower degree of lymph node metastasis (N0-N2). Similarly, expression of PCDH locus genes was down-regulated in cases of lymphoma, in metastatic samples across a number of diseases, and in diseases that commonly result in lymph node metastases including breast and lung cancer. Conclusions: Stratification of patient subgroups based on molecular signatures has become increasingly important for both assigning patients to appropriate clinical trials as well as providing insight into effective treatment options. Examination of PCDH perturbations may provide insight into a patient’s risk of developing a metastatic disease, in particular metastases to lymph nodes, and help identify patients who may benefit from a more aggressive treatment regimen.
Breast density change as a predictive surrogate for response to adjuvant endocrine therapy in estrogen receptor-positive breast cancer.
Authors: Kim Ji sun , Han Wonshik , You Jee Man , Shin Hee-Chul , Ahn Soo Kyung , Moon Hyeong Gon , Im Seock-Ah , Kim Tae-You , Cho Nariya , Moon Woo Kyung , Noh Dong Young 
Published: March 2020

e21160 Background: Previous studies showed that anti-estrogen therapy lowers mammographic breast density (MD). We hypothesized that the short-term change of breast density can be a surrogate marker predicting response to adjuvant endocrine therapy (ET) for breast cancer. Methods: We analyzed data of 1,065 estrogen receptor (ER)-positive breast cancer patients who underwent surgery between 2003 and 2006 and received at least 2 years of ET including tamoxifen and aromatase inhibitor. MD was measured using Cumulus software 4.0 and expressed as a percentage. MD reduction was defined as an absolute difference between the MD of two mammography images: taken preoperatively and 8-20months after the start of adjuvant ET.. Results: After median follow up of 68.8 months, overall recurrence rate was 7.5% (80/1065). Mean MD reduction was 5.9% (-17.2 to 36.9). In a logistic regression analysis, age<50, high preoperative MD, and longer interval between start of ET to the 2nd mammogram were significantly associated with higher MD reduction (p value<0.05). In a survival analysis using Cox model, tumor size (>2cm), lymph node positive, high Ki-67 (≥10%), and lower MD reduction were independent factors significantly associated with recurrence-free survival (p<0.05). The hazard of recurrence increased proportionally according to the less degree of MD reduction. Conclusions: MD change during short-term use of adjuvant ET was a significant predictive factor for long-term recurrence in ER-positive breast cancer. It is urgent to develop effective treatment strategy in patients who have less MD reduction in spite of about 1 year of ET.
Randomized phase III, multicenter, open-label study comparing TH-302 in combination with doxorubicin versus doxorubicin alone in subjects with locally advanced unresectable or metastatic soft tissue sarcoma.
Authors: Chawla Sant P. , Reinke Denise K. , Saks Sam , Kroll Stew , Tap William D. 
Published: March 2020

TPS10100 Background: A hypoxic microenvironment characterizes solid tumors including soft tissue sarcoma (STS) and is associated with chemotherapy resistance. TH-302, a prodrug of the alkylating agent bromo-isophosphoramide mustard (BR-IPM) is reduced in hypoxic environments, releasing Br-IPM. Combining D with TH-302 should effectively target both the normoxic and hypoxic regions of STS. TH-302 was investigated with full-dose D (75 mg/m2). The regimen was well tolerated, >60% completed 6 cycles. DLTs at higher doses were infection with neutropenia and grade 4 thrombocytopenia. The efficacy was higher than generally reported with single agent D (Sleijfer, The Oncologist, 2005). At MTD (75 mg/m2 D and 300 mg/m2 TH-302) best response were 2 (2%) CR, 30 (34%) PR, 43 (48%) SD. Median PFS and OS were 6.7 and 17.5 months, respectively. Based upon these data, a study (NCT01440088) is ongoing to assess the benefit of adding TH-302 to the standard D as first-line therapy of STS. Methods: The randomized (1:1) phase III study of TH-302 (300 mg/m2) with D versus D alone was initiated September 2011. Target goal is 450 patients. TH-302 is administered IV over 30-60 minutes on Days 1 and 8 (21-day cycle). D (75 mg/m2, bolus or continuous) is administered Day 1 starting 2-4 hrs after TH-302 when used in combination. Patients receiving TH-302 plus D without progression after 6 cycles may continue on TH-302 alone. Key eligibility criteria: locally advanced unresectable or metastatic STS untreated with chemotherapy (adjuvant allowed), ECOG 0/1, measurable disease (RECIST 1.1) and adequate hematologic, hepatic, renal function. A FDA Special Protocol Agreement was reached on study design and analyses. Primary efficacy endpoint is overall survival (OS) comparison of the combination vs D. The study is designed to detect a 40% improvement in OS with 85% power and one-sided alpha of 2.5%. An interim futility PFS analysis is scheduled after 113 PFS events. Significant improvement in PFS (one-sided p < 0.10) is required to continue. A further analysis for early efficacy stoppage is scheduled after 175 OS events. IDMC will monitor safety and efficacy.