bluuebunny/crossref_metadata_2025_split huggingface dataset:
p53 expression in breast cancer is more likely to predict survival in African-American than Hispanic or white women
Authors: Dookeran K. A. , Ferrer K. , Sekosan M. , Gao X. , Wang Y. , De La Torre R. , Lukaszczyk B. , Diaz de Leon L. , Roman G. , Zaren H. A. 
Published: March 2020

10001 Background: Abnormal nuclear accumulation of p53 protein may predict poorer survival & aggressive tumor biology in African-American (AA) women with breast cancer. We hypothesized that compared to Hispanics or whites, survival would be worse for AA women with p53 positive tumors. Methods: Tumors from 195 consecutive AA, 46 Hispanic & 52 white women were evaluated for p53 expression with IHC, using antibody Pab1801 on paraffin embedded tissue, at the SHCC MBCCOP, in Chicago. Staining was scored on the UK Receptor Group 0–8 system with score ≥2 read as positive. Survival was computed by the Kaplan-Meier method & correlated with p53 expression. Univariate analyses were done with two-sided log-rank test & multivariate analysis was done with Cox proportional-hazards model. Results: There were no significant differences between racial groups regarding tumor size, grade, node status, stage, estrogen receptor (ER) status, treatment & p53 expression. Hispanics were significantly younger (p=0.014). For AA, Hispanic & white women respectively, p53 expression was 29.2%, 34.8% & 18.8%. High grade (p=0.0001) & negative ER status (p=0.006) were significantly associated with p53 expression in AA women; similar results were seen in whites (p=0.014 & p=0.031 respectively), however although the trend for grade was similar, only negative ER status was significantly associated with p53 expression in Hispanics. AA women with p53 positive tumors had significantly worse survival compared to AA women with p53 negative tumors (Hazard Ratio=1.945; 95% CI=1.040–3.638; p=0.037). However, comparison of survival between races for women with p53 positive tumors (p=0.793) and also for women with p53 negative tumors (p=0.4027) was not different. Multivariate analysis demonstrated that there was no interaction (p=0.523) between p53 expression & stage as predictors of poor survival in AA women. Conclusions: Analyses between racial groups demonstrated that AA, Hispanic & white women with breast tumors with abnormal p53 expression had similar associations with high tumor grade, negative ER status and survival. However within racial groups, abnormal p53 expression was only able to predict significantly worse survival in AA women. This association appeared to be independent of stage. [Table: see text]
ERCC1 and RRM1 but not EGFR gene expression is predictive of shorter survival in advanced non-small cell lung cancer (NSCLC)
Authors: Selvaggi G. , Ceppi P. , Volante M. , Saviozzi S. , Novello S. , Calogero R. , Papotti M. , Scagliotti G. V. 
Published: March 2020

10030 Background: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) has been recently deeply investigated in NSCLC. Methods: We retrospectively collected 70 formalin-fixed paraffin-embedded (FFPE) bronchoscopic/fine needle aspiration biopsies of NSCLC to investigate the expression levels of ERCC1, RRM1 and EGFR by Real-Time PCR (Lord R et al. Clin Cancer Research 2002, 8:2286–91). Results were correlated with survival using the Kaplan-Meier method. Results: Sixty-one (87%) specimens were successfully amplified. Median age was 62 years (range 26–75), male/ female ratio 44/17, stage III/IV 20/41; 43 patients received cisplatin-based chemotherapy; overall median survival (MS) was 13.3 months over a median follow-up time of 45 months. ERCC1 expression level ranged from 0.70 to 15.12, RRM1 0.60–17.82. By adopting cut-off values according to median expression levels, we found a strong correlation between ERCC1 and RRM1 mRNA levels (r=0.410; p<0.001). MS in patients with low ERCC1 was significantly longer (16.9 vs 11.3 months, p<0.006) as well as in patients with low RRM1 (13.9 vs 10.9 months, p<0.03). Concomitant high expression levels of ERCC1 and RRM1 (n=26) are predictive of a worse outcome (13.9 vs 10.9 months, p<0.05). Among patients treated with cisplatin-based regimens, low ERCC1 levels were also predictive of a significantly longer MS (23.0 vs 11.6 months, p<0.002). A lower median ERCC1 level (3.2 vs 4.7) and a correlation with a better outcome were also observed in females vs males. No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression levels (range 0.5–85.8) and survival was found, even when different cut-off values were tested. Conclusions: This retrospective study further validates ERCC1 and RRM1 as good candidates genes to customize chemotherapy. Prospective studies based on the selection of patients according to genes expression levels are a research priority in early and advanced stages of NSCLC. [Table: see text]
Immature myeloid cell (ImC)- mediated immunosuppression in advanced renal cell cancer (RCC)
Authors: Kuebler H. R. , Dannull J. , Tseng T. Y. , Zhang A. , Su Z. , Dahm P. , Vieweg J. 
Published: March 2020

10042 Background: RCC affects the immunsystem by inhibiting the process of differentiation of antigen-resenting cells from their myeloid precursors by secreting tumor-derived factors such as VEGF. ImC induce a profound state of immune suppression that foster tumor tolerance by inhibition of tumor specific T cells. In this study, we asked whether increased ImC frequencies can be found in peripheral blood from RCC patients and if ImC frequencies correlated positively with increased levels of tumor-derived serum markers. Methods: ImC frequencies from healthy volunteers and RCC patients were determined by FACS. ImC were isolated by magnetic bead separation techniques and their immunosuppressive activity was determined in IFN-γ ELISPOT analyses, CTL and T-cell proliferation assays. The production of reactive oxygen species by ImC was analyzed utilizing specific probes and inhibitors. Tumor-derived serum markers were quantified by ELISA, enzyme immune assays and cytometric bead arrays. Microarray analyses were performed to identify novel, highly specific ImC markers. Results: RCC patients demonstrate higher ImC frequencies (0.8 - 3.2% of total PBMC) compared to healthy donors. The increased ImC frequencies are positively correlated with serum levels of VEGF, PGE-2, IL-13 and M-CSF in RCC patients and the concentration of byproducts of oxidative burst, including iso-prostane and malondialdehyde, was significantly enhanced. Isolated ImC exhibited profound immunosuppressive effects on CTL and CD4+ T cell response in an antigen specific fashion. Immunosuppression by ImC was mediated by release of ROS, including peroxide and superoxide anions and by generation of nitric oxide radicals as evidenced in functional assays. Results from microarray analyses reveal EP-1, EphA5, and PEX-5 as novel ImC markers. Conclusions: These data suggest that RCC may induce the development of immunosuppressive ImC population through secretion of cytokines such as VEGF, IL-13, M-CSF and PGE-2. Inhibition of specific cytokine activity or the use of differentiating agents may represent strategies to decrease immunosuppressive ImC population. Results from a phase I clinical trial investigating the effects of all-trans retinoic acid (ATRA) on differentiation of ImC in RCC patients will be presented. No significant financial relationships to disclose.
Detection of colorectal neoplasia associated K-Ras mutations in human urine
Authors: Brenner D. E. , Su Y. , Normolle D. P. , Syngal S. , Bresalier R. , Marcon N. , Baron J. , Block T. 
Published: March 2020

1005 Background: Since colorectal neoplasia-associated genes have been detected in human blood, we hypothesized that small DNA fragments containing genetic mutations associated with colorectal neoplasias are filtered and excreted in the urine. If so, genes associated with colorectal cancer will be detected in the urine. K-ras mutations are commonly associated with colorectal neoplasia and do not occur in the urinary tract. Methods: K-ras mutation detection: 200 microl of urine was extracted with guanidine thiocyanate and purifed using a Wizard DNA isolation kit. Codon 12 K-ras mutation detection methods–1: restriction enriched PCR, 20 cycles, with primers that amplify both wild type and mutated DNA but with an artificial BstNI site at the 5’ end of the amplified product (>2 K-ras copies per assay); 2: Peptide nucleic acid clamping real time PCR (>15 K-ras copies per assay). Human subjects: Training set = 20 patients with known K-ras mutations in colorectal cancer tissue. Test set = blinded urine samples from colorectal adenocarcinoma (N=48), adenoma (N=31), hyperplastic polyp (N=12) and endoscopically normal colon and rectum (N=60). Results: 1. Human urine contains 150–250 base pair DNA fragments derived from the circulation. These fragments can be readily distinguished from high molecular weight DNA from sloughed urinary tract cells. 2. Training set for K-ras detection (tissue confirmed K-ras mutations): Serum 6/20 (30%), Plasma (11/20 (55%), Urine: 18/20 (90%), (p<0.15 for plasma, p<0.001 for serum). 3. Test set (blinded): a. >2 copies of mutated K-ras genes were detected in: 16/48 (33%) adenocarcinomas; 23/31 (74%) adenomas; 5/12 (42%) hyperplastic polyps, and 19/60 (31%) non-neoplasia controls. b. >15 copies of mutated K-ras genes were detected in: 12/48 (25%) adenocarinomas; 15/31 (48%) adenomas; 3/12 (25%) hyperplastic polyps, and 11/60 (18%) non-neoplasia controls. Conclusions: Small DNA fragments in human urine contain K-Ras mutations identical to those found in colorectal cancer DNA. The sensitivity for detection of K-ras mutations in urine appears equivalent or superior to K-ras mutation detection in feces or serum. DNA mutations from systemic epithelial neoplasias may be detected in filtered urinary DNA fragments and may be useful for early detection of neoplasia. No significant financial relationships to disclose.
Lung cancer resection does not change characteristic serum proteomic profiles
Authors: Ward D. G. , Alzetani A. , Starczynski J. , Kaur G. , Trotter S. , James N. , Wakelam M. J. , Wei W. , Billingham L. J. , Johnson P. J. , Martin A. 
Published: March 2020

10051 Background: Surface-enhanced laser desorption/ionisation time of flight mass spectrometry (SELDI-TOF-MS) has been proposed as a method for determining characteristic serum proteomic profiles that permit discrimination between cancer and non-cancer patients. The aim of this study was to test in a group of lung cancer patients the hypothesis, that these profiles ‘return to normal’ following tumour resection, as would be expected if they behave as conventional serological tumour makers. Methods: Serum samples were collected from 39 patients with non-small cell lung cancer, 1 day pre-surgery, 1 day post-surgery and, for 17 of these, approximately three months later; samples were also obtained from 38 non-cancer control subjects. All samples were subjected to SELDI-TOF-MS analysis on CM10 chips. Students t-tests were used to identify differentially expressed peaks in the profiles. Results: The SELDI profiles of the lung cancer sera compared to non-lung-cancer controls showed 19 significantly differentially expressed peaks (p<0.01), 14 of which were used to develop a neural network capable of discriminating between the two groups. Analysis of proteomic features showed that despite the absence of cancer in patients 3-months post-surgery, no statistically significant differences could be detected between the pre-treatment and 3-month post-operative samples from the same patients, including the 19 features that were found to discriminate between lung and non-lung cancer. One of the proteins significantly decreased in the serum of lung cancer patients was identified as transthyretin. Conclusions: SELDI can detect differentially expressed protein peaks characteristic of lung cancer compared to non-lung cancer patients but following surgical resection of the cancer, neither the pattern nor the individual peaks revert to the levels observed in non-lung cancer patients. The hypothesis that such differences would revert to normal after tumour removal was not supported. Work funded by Cancer Research UK No significant financial relationships to disclose.
Detection of clinically significant mutations in the epidermal growth factor receptor missed by direct sequencing using a highly sensitive DNA endonuclease
Authors: Borras A. M. , Kuang Y. , Rogers A. M. , Holmes A. J. , Gallegos Ruiz M. , Joshi V. A. , Distel R. J. , Giaccone G. , Taron M. , Janne P. A. 
Published: March 2020

10054 Background: Mutations in the epidermal growth factor receptor (EGFR) are associated with sensitivity and resistance to EGFR inhibitors gefitinib and erlotinib in patients with non-small cell lung carcinoma (NSCLC). Direct sequencing is currently used for mutation detection but sensitivity is limited and requires dissection to obtain a relatively pure population of tumor cells. We examined a DNA endonuclease, SURVEYOR, which cleaves mismatched heteroduplexed DNA, as a more sensitive method for EGFR mutation screening and compared it to direct sequencing. Methods: EGFR exons 18–21 from tumor DNA were amplified using PCR, digested with SURVEYOR, and the products analyzed by HPLC. Specimens that produced digestion products were re-analyzed by size separation or by denaturing HPLC followed by fractionation and sequencing. Tumor specimens from 191 NSCLC patients were analyzed: 61 frozen tumors specimens; 91 dissected formalin fixed paraffin embedded (FFPE) and 39 un-dissected FFPE tumor specimens from patients treated with gefitinib or erlotinib in whom clinical outcome was available. 173 specimens were independently analyzed by direct sequencing. Results: We detected 48 EGFR mutations by sequencing and 61 using SURVEYOR. All EGFR mutations identified by sequencing, including those using un-dissected tumor specimens, were detected by SURVEYOR and none were missed (sensitivity: 100%, negative predictive value: 100%). 13 mutations were detected by SURVEYOR not detected by sequencing. This included 5 mutations (4 exon 19 deletions; 1 L858R) in 7 (71%) patients who clinically had a PR to gefitinib or erlotinib but who were wild type by sequencing. In 4 patients, 2 with clinical acquired resistance to gefitinib, a T790M mutation was found which was undetected by sequencing. Conclusions: SURVEYOR analysis is a more sensitive method for EGFR mutation detection than direct sequencing. It can be used to detect EGFR mutations from un-dissected tumor specimens and can detect clinically significant activating or resistance associated EGFR mutations not detected by direct sequencing. [Table: see text]
Molecular network analysis of signaling pathways in metastatic breast cancer in patients treated with erlotinib
Authors: Speer R. , Wallwiener D. , Yang S. X. , Swain S. M. , Wulfkuhle J. D. , Liotta L. A. , Petricoin E. F. 
Published: March 2020

10064 Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is under active clinical investigation. It may have profound effects on the cellular molecular network by affecting downstream signaling and inhibiting tumor cell proliferation. Knowledge about the specificity of drug effects on the signaling pathways might enable therapy tailored specifically for each patient’s defect. We examined the activation of cellular signaling pathways involved in cell survival and proliferation in response to erlotinib treatment using a biopsy study set that comprised patient-matched breast cancer metastases from 8 women obtained prior to treatment with erlotinib and after 1 month of therapy. We procured pure cancer cell lysates from very small amounts of frozen tissue by Laser Capture Microdissection (about 60,000 cells). Matching lysates were printed on nitrocellulose and incubated with antibodies against the endpoints of interest. Using the Reverse Phase Protein Microarray technology we were able to generate a portrait of 18 phosphorylated kinase substrate endpoints as well as total expression levels of ERK, EGFR, Her2/neu, and IGF1R that revealed an upregulation of pro-survival pathway signaling in the post-erlotinib treatment set. Especially the measurement of the pro-survival, apoptosis-inhibiting signal transduction pAkt (S473) protein alone showed a statistically significant stronger staining in post-erlotinib treatment samples (p=0.019) in each of the individual patient-matched specimens as well as the entire post-treatment group, showing concordance with the clinical data of the trial, i.e. progressive disease observed for all participating patients. The results indicate the feasibility of this approach to monitor signaling events and molecular pathways in clinical specimens taken during targeted therapy trials. No significant financial relationships to disclose.
An AS04-containing human papillomavirus (HPV) 16/18 vaccine for prevention of cervical cancer is immunogenic and well-tolerated in women 15–55 years old
Authors: Schwarz T. F. 
Published: March 2020

1008 Background: Genital HPV infections can be acquired shortly after sexual debut, and the risk remains throughout a sexually active woman’s lifetime. In women 15–25 years of age, the AS04-containing HPV vaccine was highly immunogenic and conferred 100% protection against HPV-16/18 persistent infection and associated cervical lesions up to 27 months. In the long-term follow-up of this study, sustained vaccine efficacy has been observed up to 48 months. The present phase III study (580299/014) assessed immune responses to the AS04-containing HPV-16/18 vaccine in women 26–55 years old compared with women 15–25 years old. Methods: Healthy women in Germany and Poland between 15 and 55 years of age received 3 doses of HPV-16/18 AS04-containing vaccine at months 0, 1, and 6. The groups were age stratified: 15–25 (n=229), 26–45 (n=226), and 46–55 (n=211). Anti-HPV-16/18 antibody titers were assessed at months 0, 2, 7, and 12 by ELISA (EU/mL). Seropositivity rates and geometric mean antibody titers (GMTs) were calculated for all groups. Safety was assessed after each dose in all participants. Results: All initially seronegative women became seropositive for both HPV 16 and 18 at Month 2. At Month 7, HPV-16 GMTs (95% CI) were 7908.4 (6874.0–9098.5) in 15–25 year olds, 4029.2 (3402.7–4771.0) in 26–45 year olds, and 2566.8 (2181.2–3020.6) in 46–55 year olds. For HPV-18, GMTs were 3499.3 (3098.7–3951.6) in 15–25 year olds, 1837.3 (1602.1–2107.0) in 26–45 year olds, and 1313.0 (1145.6–1504.9) in 46–55 year olds. Overall the vaccine was well-tolerated, and the incidence of local symptoms (within 30 days) tended to be lower in the 46–55 year-old group (69.2% versus 81.6% [26–45] and 85.7% [15–25]). Conclusions: An AS04-containing HPV-16/18 vaccine was immunogenic and generally safe in 15–55 year-old females. As observed with other vaccines, GMTs decreased with age, however, the Month 7 postvaccination antibody levels in the oldest age group (46–55) were still 3–4 times higher than those observed during a separate long-term follow-up study where sustained efficacy has been observed up to 48 months. [Table: see text]
Shc test as a strong prognostic indicator of disease outcome in early stage gastric cancer
Authors: Wanebo H. J. , Frackelton A. R. , Hafer L. J. , Bagdasaryan R. , Lis R. , Sabo E. , Resnick M. B. 
Published: March 2020

10090 Background: Treatment planning for gastric cancer is primarily based on clinical staging of disease. Markers predicting likelihood of disease outcome would help guide treatment decisions, especially for early stage disease. The Shc proteins, implicated in many aggressive cancers, and measured in tumor specimens by the immunohistochemical (IHC) Shc Test, have shown strong ability to predict disease outcome in breast cancer. We report here that the Shc Test is a strong prognostic indicator of disease outcome in early stage gastric cancer. Methods: Histopathology was examined in one hundred and seventeen (117) primary gastric cancer patient samples from Rhode Island Hospital in tissue microarray format (21 disease recurrences; 63 disease-specific deaths; average follow-up of 2.7 yrs). IHC staining of the Shc proteins was independently scored on a 0–5 scale by two pathologists, blinded to patient information. Results: Stage I or II gastric cancers (n=62) could be clearly separated at a cutpoint of 1.1 on a 0–5 scale, into good prognosis (16% 4yr relapse risk; demonstrating high PY-Shc) and poor prognosis (46% 4yr relapse risk; showing low PY-Shc) (log-rank, P=0.003). p66 Shc showed similar prognostic abilities. High PY-Shc in patients with early stage disease showed a significant protective effect on overall survival (P=0.003) by univariate log rank analysis. As a continuous variable, PY-Shc had a strong predictive ability (HR = 0.09, P=0.055) that approached significance. By univariate Cox proportional hazards, patients with high PY-Shc had a 5-fold reduction in disease specific death (DSD) compared to patients with low PY-Shc (P=0.002). By multivariate Cox proportional hazards, adjusted for grade, stage, chemotherapy and radiation therapy, only PY-Shc (HR = 0.22, P=0.015) and Intestinal tumor type (HR = 0.38, P=0.046) remained as significant predictors of survival. Conclusions: The Shc Test shows a strong prognostic ability to stratify early stage gastric cancer patients by risk, making it a valuable tool in selecting therapy for these patients. [Table: see text]
PAI-1 (Plasminogen activator inhibitor-1) expression levels in colorectal cancers and corresponding normal tissues
Authors: Sakakibara T. , Hibi K. , Koike M. , Fujiwara M. , Kodera Y. , Nakao A. 
Published: March 2020

10094 Background: We performed a quantitative RT-PCR for Plasminogen Activator Inhibitor-1 (PAI-1) gene in 55 surgical specimens of colorectal cancer (CRC) and corresponding normal mucosa. To test the hypothesis that PAI-1 may serve as a candidate marker for the malignant potential of CRC, we evaluated the possible relationship between PAI-1 gene expression levels and clinicopathological findings in CRC. Next, to investigate the mechanism of PAI-1 overexpression in CRC, we compared the PAI-1 expression levels in these cancers with those in the corresponding normal tissues. Results: A significant increase in PAI-1 expression scores was observed in node-positive CRCs (2.19Å}0.43) compared to negative ones (0.35Å}0.42) (P=0.0037) as well as in CRCs with distant metastasis (3.50Å}1.18) compared to negative ones (0.99Å}0.30). A significant increase in PAI-1 expression scores was observed in lymph node metastasis-positive CRCs (2.19Å}0.43) compared to negative ones (0.35Å}0.42) (P=0.0037) as well as in distant metastasis-positive CRCs (3.50Å}1.18) compared to negative ones (0.99Å}0.30). The PAI-1 expression score markedly increased with the tumor stage (P=0.0063; ANOVA test). Moreover, multivariate analysis revealed the PAI-1 expression score to be a strong and independent prognostic factor for CRC (P=0.0432). There was a significant correlation between CRC and corresponding normal PAI-1 expressions with a Spearman’s rank correlation coefficient of 0.81 (P < 0.0001). Conclusion: These results suggested that PAI-1 might serve as a new parameter for the prediction of prognoses in CRC. Taken together, PAI-1 overexpression in CRCs might originate from higher PAI-1 expression in the corresponding normal tissues and result in a malignant phenotype of these cancers. No significant financial relationships to disclose.