bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of Epstein-Barr Virus DNA load detected pre- and post-radiotherapy in nasopharyngeal carcinoma patients
Authors: Hou X. , Zhang L. , Zhao C. , Lu L. , Han F. , Li S. , Huang P. , Huang H. , Guan Z. 
Published: March 2020

10558 Background: Plasma Epstein-Barr virus DNA (EBV DNA) load has been shown to be clinically useful in the detection, monitoring, and prognostication of nasopharyngeal carcinoma (NPC). However, the clinical significance of EBV DNA load detected at different time points has not been addressed to our knowledge. In this study, we investigated whether pre- and post-treatment plasma EBV DNA load have different prognostic implications in NPC patients who were treated with radiotherapy. Methods: Plasma samples from 69 patients with primary NPC were collected before and after radiation treatment, and subjected to a real-time quantitative polymerase-chain- reaction assay of EBV DNA load. The pre-treatment primary tumor volume (GTVnx) calculated through CT images and/or MRI were documented. All patients were scheduled to follow up. Results: The pre-treatment plasma EBV DNA concentration was significantly associated with primary tumor volume (Spearman correlation coefficient=0.614; P=0.000). With a cutoff value of 20,000 copies/ml and 0 copies/ml respectively for pre-treatment and post-treatment plasma EBV DNA copy number, patients with lower EBV DNA concentrations had statistically preferable progression-free survival,metastasis-free survival and overall survival compared with those with higher EBV DNA concentrations. Cox regression analysis demonstrated that both pre-treatment EBV DNA load (P=0.050;RR=3.95) and post-treatment EBV DNA load (P=0.001;RR=11.74) were risk factors for metastasis-free survival. When further integrating pre-treatment with post-treatment concentration of EBV DNA, it was demonstrated that whether EBV DNA concentration could be dropped to 0 after treatment dominate the prognostic effect for metastasis-free survival (P=0.000). Conclusions: Pre- and post-treatment plasma EBV DNA have different clinical significance. Pre-treatment plasma EBV DNA is a reliable molecular marker reflecting primary tumor volume. While the clearance of circulating plasma EBV DNA after treatment is a good predictive marker of freedom from distant metastasis. No significant financial relationships to disclose.
An investigational rapid RT-PCR assay for the detection of metastasis in sentinel lymph nodes shows improved performance over frozen section H&E: Analysis by primary tumor characteristics
Authors: Blumencranz P. , Deck K. B. , Whitworth P. W. , McCue P. , Reintgen D. S. , Beitsch P. , Chagpar A. S. , Julian T. B. , Mamounas M. , Simmons R. 
Published: March 2020

10561 Background: In order for a RT-PCR test to accurately diagnose the metastatic status of sentinel lymph nodes the test must perform well across all primary tumor types. Methods: A prospective study was conducted at 11 clinical sites to evaluate a real- time RT-PCR assay (investigational GeneSearch™ Breast Lymph Node Assay, Veridex, LLC, Warren, NJ, USA) for the detection of sentinel lymph node metastasis in patients with invasive breast cancer. Detection limits were pre-set to detect only metastases that are clinically relevant (> 0.2 mm). Tumor information such as tumor stage, size, type and other molecular characteristics were collected. RT-PCR assay was then compared against permanent section H&E and IHC for final performance calculations. A total of 416 patients’ results were analyzed for overall assay performance: sensitivity 87.6% and specificity 94.2%. The assay was then evaluated within each primary tumor characteristics category. Results: Overall RT-PCR sensitivity is an improvement (p= 0.039) over that of current intra-operative methods (frozen section H&E), while specificity is similar (p=0.054). For the various tumor sub-types, in a matched dataset, the RT-PCR assay has up to 35.7% (Invasive Lobular) higher sensitivity compared to frozen section H&E. Conclusions: The data suggest that the RT-PCR assay performs well and has higher sensitivity than frozen section H&E regardless of primary tumor characteristics and, therefore, can be used to detect metastasis for all types of invasive breast cancer. [Table: see text] No significant financial relationships to disclose.
The effect of P53 gene status on the interaction of vorinostat (Suberoylanilide Hydroxamic Acid-SAHA) with carboplatin in non-small cell lung cancer (NSCLC) cell lines
Authors: Hershberger P. , Owonikoko T. K. , Ramalingam S. , Belani C. P. 
Published: March 2020

10567 Background: Vorinostat, a Histone Deacetylase (HDAC) inhibitor is a novel targeted antineoplastic agent with promising activity when combined with carboplatin-paclitaxel against NSCLC. The exact molecular mechanism underlying its growth inhibitory and apoptotic effects is not well understood. We investigated the influence of p53 gene status on the interaction of vorinostat and carboplatin (a DNA targeting agent) in various NSCLC cell lines. Methods: NSCLC cells with wild type p53 (A549, 128.88T), mutant p53 (201T) and p53 null phenotype (Calu-1) were used. Cytotoxicity induced by serial dilution of carboplatin in the presence and absence of a fixed dose (1μM) of vorinostat was assessed by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay. In a separate experiment, cells were also transiently transfected with a p21 promoter-luciferase reporter construct to assess p53 activation following a 24 h exposure to vorinostat, carboplatin, or vorinostat/Carboplatin combination. Luciferase activity was quantified by luminometry and corrected for total protein. Results: Vorinostat displayed single agent activity in each cell line, with greater growth inhibition observed in the p53 mutant and null cells. Synergistic interactions between carboplatin and vorinostat were observed in p53 wild type cells and the IC50 for carboplatin was reduced 3- to 5-fold. In contrast, the interaction between vorinostat and carboplatin was additive or less than additive in p53 mutant and p53 null cells. Vorinostat also increased expression of the p21 reporter construct in each of the cell lines. Conclusions: Vorinostat regulates p21 gene expression and elicits anti-tumor activity in NSCLC cells independent of their p53 status. Vorinostat potentiates carboplatin-induced cytotoxicity in NSCLC with wild type p53 but not p53 deficient cells, suggesting involvement of a p53 dependent pathway. The addition of vorinostat may allow for a reduction in standard dose of carboplatin with improvement in overall therapeutic index. A phase II/III clinical trial is in progress to evaluate vorinostat in combination with carboplatin-based regimen in advanced NSCLC. Support: CA099168–01, ASCO Foundation CDA No significant financial relationships to disclose.
Expression and activation of mTOR in neuroendocrine tumors. Effects of mTOR inhibition by RAD001 upon growth, cell cycle regulation and signalling in neuroendocrine cell lines
Authors: Hörsch D. , Tielke S. , Schrader J. 
Published: March 2020

10570 Background: Molecular pathogenesis of neuroendocrine tumors of the digestive tract is largely unknown. We examined paraffin sections of different types of neuroendocrine tumors for expression of activated kinases involved in regulation of growth and protection against apoptosis. In addition, we studied effects of a newly developed inhibitor of mTOR (RAD001) upon growth, cell cycle regulation and signaling in two different neuroendocrine cell lines. Methods: Immunohistochemistry with antibodies for native and activated signaling kinases was performed on paraffin sections. MTT assays were used to determine growth rates of neuroendocrine cell lines and FACS analysis was performed for cell cycle analysis. Immunoblotting revealed activation of kinases. Results: Extracellular activated kinase 1/2 (ERK1/2), cAMP regulated element binding protein (CREB), protein kinase B (PKB) and mTOR were expressed in the majority of insulinomas (n = 40) and serotonin-producing neuroendocrine tumors (carcinoids, n = 49). Phosphorylated forms of these kinases corresponding to their activated state were also detected in these tumors. Most neuroendocrine tumors expressed high levels of activated CREB, PKB and mTOR whereas phosphorylated ERK1/2 was present only a minority of dNETs. Inhibition of mTOR kinase by different concentrations of RAD001 induced growth arrest in insulinoma (INS-1) and human neuroendocrine serotonin-producing cells (BON) in concentrations between 10 and 100 nM. Interestingly, we observed pronounced synergism between octrotide and RAD001 upon growth inhibition in these cell lines. Growth inhibition by RAD001 corresponded to decreased S-phase and increased G0/G1 peak in cell cycle analysis. RAD001 inhibited effectively phosphorylation of mTOR with an IC50 of 10 nM. However, we observed only minor inhibition of PKB and CREB by RAD001 and partial inhibition of ERK signaling by RAD in concentrations between 100 nM and 1 μM. Conclusions: mTOR is expressed and activated in different neuroendocrine tumors and inhibition of mTOR by RAD001 induces growth inhibition, cell cycle arrest and decreased signaling by mTOR and ERK1/2 in neuroendcrine cell lines INS-1 and BON. No significant financial relationships to disclose.
Overexpression of chemokine receptor CXCR4 in cancer specimens following neoadjuvant chemotherapy predicts outcome in patients with locally advanced breast cancer (LABC)
Authors: Holm N. T. , Byrnes K. , MacDonald M. , Abreo F. , Ampil F. , Sanders M. , Burton G. V. , Li B. , Chu Q. 
Published: March 2020

10578 Background: Despite significant advances made in the treatment of locally advanced breast cancer (LABC) with neoadjuvant chemotherapy, a significant number of patients continue to die. A molecular predictor to identify those who are at an increased risk for relapse is sorely needed. CXCR4 is a chemokine receptor that has been linked to breast cancer invasion and metastasis. We postulate that CXCR4 overexpression levels in cancer specimens following neoadjuvant chemotherapy predict cancer outcome in patients with LABC. Methods: 54 patients with LABC were prospectively accrued and analyzed. All had neoadjuvant chemotherapy, followed by definitive surgical and adjuvant chemo-radiation therapy. Study homogeneity was maintained by standardized treatment, surveillance, and compliance protocols. A 1 cm 3 cancer from the surgical specimens of each patient was retrieved for analysis. CXCR4 levels were detected using Western blots and results were quantified against 1 μg of HeLa cells (positive controls). CXCR4 expression was defined as low (<6.6 fold) or high (= 6.6 fold). Primary endpoints were cancer recurrence and death. Statistical analysis performed included Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model. Results: With a median follow-up of 30 months, patients whose tumors had high CXCR4 overexpression (= 6.6 fold) had a statistically significantly higher incidence of recurrence (p= 0.0009) and cancer-related death (p= 0.0168) than those in the low CXCR4 group (< 6.6 fold). After adjusting for tumor size, nodal status, ER, PR and HER-2 status, the relative risk for recurrence and death in the high CXCR4 group was 27.3-fold (p=0.001; 95% CI: 6.2 to 120.8) and 4.8-fold (p=0.0076; 95% CI: 1.5 to 15.0) higher than those in the low CXCR4 group, respectively. Conclusion: High CXCR4 overexpression in cancer specimens following neoadjuvant chemotherapy was highly predictive of cancer recurrence and cancer death in patients with LABC. No significant financial relationships to disclose.
Vinflunine in combination with trastuzumab for treatment of HER2-positive metastatic breast cancer
Authors: Paridaens R. , Wildiers H. , Dalenc F. , Rixe O. , Cadic V. , Pinel M. , Roche H. 
Published: March 2020

1058 Background: Vinflunine (VFL) is a microtubule inhibitor of the vinca alkaloid class with high activity in several tumour types especially in second line treatment of metastatic breast cancer (MBC). Over-expression of HER2 is observed in 20–25% of all breast cancers and is associated with a poor prognosis. The development of the anti-HER2 therapy with trastuzumab (T) allowed significant prolonging of the survival in HER2 positive MBC. The combination of these two compounds which are separately active in MBC warranted a combination study. Methods: This phase I was designed to determine the recommended dose (RD) of VFL in combination with T for treatment of first or second line MBC patients (pts), to assess its safety profile, and to determine its antitumour activity. Results: Thirty pts, median age 55 [33–74] years, WHO performance status 0/1: 18/12 pts , respectively were given VFL 280 mg/m2 (10 pts) or 320 mg/m2 (20 pts) day 1 every 3 weeks (w) in combination with T (loading dose 4 mg/kg and subsequently 2 mg/kg/w). Six pts were chemonaive and 5 pts received this combination in second line. At the first VFL dose (280 mg/m2), 0/6 pts experienced dose-limiting toxicity. The RD was established at 320 mg/m2 in the following 6 pts. All 30 pts are evaluable for safety. Haematological toxicities were: anaemia grade (G) 3: 0 and 1 pt; neutropenia G 3/4: 5/17 pts, febrile neutropenia 0/2 pts with VFL 280 and 320 mg/m2, respectively. G 3 non-haematological adverse events were only reported in the 20 pts receiving VFL 320 mg/m2: fatigue and myalgia: 5 pts; constipation: 4 pts; abdominal pain, neutropenic infection: 2 pts. ileus, hyponatremia, arthralgia: 1 pt. No significant cardiac events were observed. The response rates, 62.5% [95% confidence interval: 24.5–91.5] and 73.7% [95% confidence interval: 48.8–90.9] in pts receiving VFL at 280 mg/m2 and 320 mg/m2 respectively, were established by an external radiologist using RECIST in the first 27 evaluable patients. Conclusions: Vinflunine/trastuzumab combination is feasible with encouraging response rates and manageable toxicity in MBC pts. A phase III study comparing VFL + T versus paclitaxel + T has been initiated. No significant financial relationships to disclose.
Stage III colon cancer prognosis prediction by gene expression profiling
Authors: Barrier A. , Boelle P. , Brault D. , Houry S. , Lacaine F. , Flahault A. , Dudoit S. , Lemoine A. 
Published: March 2020

10590 Background and Aims: Postoperative chemotherapy has become part of the standard treatment for stage III colon cancer patients. Since approximately half of patients are cured by surgery alone, adjuvant chemotherapy should not be used in all patients. This study aimed to assess the possibility to use microarray-based gene expression profiles to predict the prognosis of stage III colon cancer patients. Material and Methods: Forty-two patients operated on for a stage III colon cancer were included in this study. Twenty-one patients have received an adjuvant chemotherapy, while the other 21 have received no treatment. Twenty patients have developed a liver metastasis, while the other 22 have remained disease-free for at least 5 years. Tumor mRNA samples were profiled using the Affymetrix HGU133A GeneChip. Two analyses were performed: one with the 42 patients, the other with the 21 patients who did not receive any adjuvant chemotherapy. For each analysis, patients were repeatedly and randomly divided into 10,000 training (TS) and validation sets (VS) of 10 different sizes. For each TS/VS split, a 30-gene prognosis predictor (PP), identified on the TS, was used to predict the prognosis of VS patients. Performances of a 15-gene PP and a 34-gene PP, proposed by another research team, were also assessed on the same TS and VS. Results: First analysis (42 patients). The 10,000 30-gene PP yielded the following average prognosis prediction performance measures: 73.8% accuracy, 74.6% sensitivity, and 73.0% specificity. Improvements in prognosis prediction were observed with increasing TS size. A total of 4,446 genes were included in the 10,000 PP. The 15-gene PP yielded a 69.7% accuracy; the 34-gene PP yielded a 71.2% accuracy. Second analysis (21 patients). The 10,000 30-gene PP yielded the following average prognosis prediction performance measures: 77.7% accuracy, 75.8% sensitivity, and 79.9% specificity. Improvements in prognosis prediction were observed with increasing TS size. A total of 5,478 genes were included in the 10,000 PP. The 15-gene PP yielded a 78.5% accuracy; the 34-gene PP yielded a 81.9% accuracy. Conclusion: Microarray gene expression profiling is able to predict the prognosis of stage III colon cancer patients and, thus, might be used for an appropriate use of adjuvant chemotherapy. No significant financial relationships to disclose.
Elevated serum M-CSF level predicts reduced survival in metastatic breast cancer patients
Authors: Leitzel K. , Ettenberg S. , Walsh R. , Abraham J. , Modur V. , Braendle E. , Evans D. B. , Ali S. M. , Demers L. , Lipton A. 
Published: March 2020

10591 Background: Macrophage colony stimulating factor (M-CSF) and its receptor (CSF-1R, the c-fms oncogene protein product) have been reported to be expressed in a variety of cancers, including breast cancer. The M-CSF produced by breast cancer cells and surrounding stromal cells increases osteoclast formation and maturation and enhances the expression of stromal RANK ligand, both of which increase osteolytic bone degradation. In this study we evaluated the predictive and prognostic potential of circulating M-CSF in metastatic breast cancer patients treated with hormone therapy. Methods: Using an M-CSF ELISA (R&D Systems, Minneapolis, MN), M-CSF concentration was determined in pretreatment sera from 204 metastatic breast cancer patients enrolled in a phase III 2nd-line hormone therapy trial of fadrozole vs. megace, and also in sera from 25 post-menopausal control female subjects. Results: The serum M-CSF level from the 25 healthy post-menopausal female control subjects had a mean ± SD of 835.6 ± 276.1 pg/ml (range 319.0 - 1,465.8 pg/ml). The upper limit of normal was defined as the 95th percentile of the serum M-CSF level from the female control group (1277 pg/ml). Pretreatment serum M-CSF levels from the metastatic breast cancer patients ranged from 82.2 - 3,019.8 pg/ml, and were found elevated above the upper limit of normal in 15 of 204 patients (7.35 %). Patients with elevated pretreatment serum M- CSF did not have a significantly different objective response rate, clinical benefit rate, or time to progression to hormone therapy; but these patients did have significantly reduced overall survival (median survival 10.0 months) compared to patients with normal serum M-CSF levels (median survival 24.3 months)(p = 0.007). In multivariate analysis with serum HER-2/neu included as a covariate, elevated serum M-CSF level remained a significant independent variable for reduced survival (p= 0.032). Conclusions: Pretreatment serum M-CSF levels were elevated in 7 % of metastatic breast cancer patients compared to healthy female control subjects, and these patients had significantly reduced overall survival. Serum M-CSF deserves further study to determine its predictive and prognostic biomarker potential in breast cancer patients. No significant financial relationships to disclose.
Association between expression of insulin resistance (IR) related genes and breast cancer outcome
Authors: Gennari A. , Sormani M. , Pronzato P. , Bruzzi P. , Ferrannini E. , Iozzo P. , Roncella M. , Ghilli M. , Mirisola V. , Pfeffer U. 
Published: March 2020

10597 Background: IR is associated with adverse outcome in breast cancer. IR may affect patient outcome via the insulin and the IGF axis, acting through the tyrosine kinase signaling in enhancing cell proliferation. To date, no study explored the role of insulin- related gene expression in breast cancer progression. The aim of this study was to evaluate the prognostic value of a set of insulin-related genes using published microarray datasets. Methods: IR genes were sorted according to the “insulin sensitivity gene set” previously defined in peripheral tissues of healthy subjects screened for IR by the euglycaemic insulin clamp technique. One-hundred-forty- three genes were used to develop an outcome predictor on a training set of 102 primary breast tumors, randomly selected from 159 patients in the GEO database ( GSE1456 ). The outcome predictor was validated on the remaining 57 patients. Primary outcome measure was relapse free survival (RFS). Univariate non-parametric Mann-Whitney U test was used to identify genes differentially expressed. Expression of genes significantly correlated with relapse was combined in a linear score. Patients were classified as low or high risk with respect to the median score. Kaplan-Meier curves were used to evaluate the discriminating power of the score. Results: Fourteen genes resulted differentially expressed in the training set: the 8-year RFS was 91% (SE =4%) and 51% (SE = 8%) in the low risk and high risk group, respectively (p < .001). In the validation set, the 8-year RFS was 97% (SE = 3%) and 54% (SE = 10%), respectively (p = .009), supporting the discriminating ability of the score. By multivariate Cox analysis, the prognostic ability of the score was independent of subtype and grade (p < .001). Conclusions: Our data provide the first evidence that expression of insulin related genes can predict outcome, and indicate that the insulin pathway is involved in breast cancer progression. This is particularly important since IR is responsive to lifestyle interventions. We are currently validating the insulin-related score on independent breast cancer microarray datasets. No significant financial relationships to disclose.
A new estrogen receptor on ER-negative breast cancer?
Authors: Peralta E. , Paris B. D. , Kamel O. W. , Louis S. , Dunnington G. L. 
Published: March 2020

10604 Background: Premenopausal women and BRCA-1 mutation carriers have estrogen receptor-negative (ER-) breast cancers that paradoxically seem responsive to hormonal deprivation such as oophorectomy. GPR30 is a G protein-coupled receptor that is activated not only by estradiol but also tamoxifen and fulvestrant. The prevalence and significance of GPR30 in breast cancer are unknown. We hypothesized that GPR30 may be present in ER-negative tumors and may promote growth of ER-negative breast cancer in premenopausal patients. Methods: An immunohistochemical staining protocol for rabbit polyclonal GPR30 antibody (Novus Biological) was developed initially on the known GPR30-positive breast cancer cell line MCF-7 and the GPR30-negative breast cancer cell line MDA-MB-231 and later on a panel of human breast tumors from archived paraffin blocks. After an automated protocol was optimized, under an IRB-approved protocol all incoming breast cancer specimens were stained for GPR30 and reviewed by a pathologist blinded to the ER/PR status. Significance of associations was tested by chi square analysis. Results: Twenty-seven breast cancer tumors were studied. The mean age of the patients was 53 (range 20–87). All of 10 triple negative (ER-,PR-, HER2 neu-) and 2 ER-/Her2 neu+ tumors stained positive for GPR30. Only 4 of 11 ER+/Her2neu - tumors stained positive for GPR30 (p=0.004). The mean age of triple negative patients was 43.7 yr, while the mean age of ER+/Her2 neu- was 63.2 (p=0.02). Three out of 4 ER+/HER2 neu+ tumors stained positive for GPR30. Four patients were African Americans, 2 had triple negative tumors and 2 ER+/Her2+, all 4 were positive for GPR30. Conclusions: GPR30 appears to be frequently expressed in ER-negative breast cancer and may represent an adverse factor. ER+ tumors with good prognostic features (PR+, HER2 neu-) were mostly negative for GPR30, while high-risk tumors were positive for GRP30. Premenopausal status and African-American race are known risk factors for lower survival. In this study, the African-American patients had high-risk tumors that were also positive for GPR30. A longer- range study is needed to test the association of GPR30 expression with recurrence and death. Future studies to assess the function of GPR30 in breast cancer cells may yield prognostic and therapeutic applications. No significant financial relationships to disclose.