bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bevacizumab and irinotecan in patients (pts) with recurrent glioblastoma multiforme (GBM)
Authors: Raval S. , Hwang S. , Dorsett L. 
Published: March 2020

2078 Background: Primary GBM exhibits overexpression or amplification of the epidermal growth factor gene. The effectiveness of bevacizumab and irinotecan in pts with relapsed GBM was first reported in 2005 (Stark-Vance, et al, Neuro-Oncol, 2005). In this report, we assess the effects of combination of bevacizumab and irinotecan on overall responses, toxicity, cognitive function and functional status in recurrent GBM pts. Methods: From August 2005 to December 2006, 22 consecutive GBM pts failed > 1 prior chemotherapy with measurable disease on MRI were included. Each patient received bevacizumab 5mg/kg IV and irinotecan 125mg/m2 IV infusion every 2 weeks until disease progression or developed unacceptable toxicity. The response was determined by MRI every 2 cycles. Cognitive function was assessed by Blessed Orientation-Memory-Concentration Test (BOMC) and functional status was assessed by Karnofsky performance status (KPS), Barthel Index (BI) and Instrumental Activities of Daily Living (IADL) prior to each cycle of treatment. Descriptive statistics analysis was used. Results: All pts failed temozolomide and radiation therapy; 1 pt had prior BCNU and 2 pts had prior irinotecan treatment. The median (M) age was 55 years (37-77) with pre treatment M KPS 80 (40–80), BOMC 7 (0–28), BI 85 (10–100) and IADL 6 (0–17); 12 pts exhibited mild (3 pts), moderate (7 pts) to severe (2 pts) cognitive impairment. The M number of cycles received was 8 (2–27); 21 pts are evaluable for MRI responses with 95.2% response rate (2CR’s + 14PR’s + 4 minimal responses). Seven pts have expired; the M length of survival was 4.6 months (range 1.1–15.4+) and the M time to progression was 3 months (0.5–13.8+). There were only two grade 3 thrombocytopenia and one grade 3 neutropenia. Improvement in BOMC score was seen in 15 pts (62%) with M improvement of 7 point. Improvement in functional status was seen in 18 pts (85.7%) with M improvement in KPS by 10 point, BI by 8 points and IADL by 2 point. Conclusions: The combination of bevacizumab and irinotecan is well tolerated and safe. The overall response rate was 95.2% and significant improvements in cognitive functional and functional status were demonstrated. The longer follow up will determine the impact of this most active combination. No significant financial relationships to disclose.
COM-1 is over-expressed in human colorectal carcinomas
Authors: Davies M. L. , Watkins G. , Torkington J. , Fodstad O. , Jiang W. G. 
Published: March 2020

21001 Background: COM-1, candidate of metastasis-1, is a primarily nuclear protein thought to play a role in the development and maintenance of metastatic tumours and to have some mitogenic activity. However subsequent investigations have demonstrated a much more diverse role in cancer and cell growth. Here we have investigated the expression and sub-cellular distribution patterns of COM-1 in human colorectal carcinomas. Methods: Carcinoma and normal matched tissues were collected following surgery and frozen for future analysis. Sections of tissue underwent immuno-histochemistry (IHC) staining for COM-1 to determine degree of staining and changes in cellular distribution of the proteins within the tissue. Furthermore, quantitative analysis (quantitative polymerase chain reaction - qPCR) of mRNA levels of COM-1 transcripts was performed to compare levels in normal tissue with those in carcinoma tissues. Statistical analysis was by the Mann-Whitney test. Results: IHC -Normal tissue demonstrated strong nuclear staining for COM-1 protein with little or no cytoplasmic staining. In carcinoma tissue the level of overall staining was found to be much greater, with a greater degree of cytoplasmic staining and little evidence of nuclear staining. qPCR- COM-1 mRNA expression within cells was significantly higher within tumour tissue when compared to normal tissue (Mean 36.7 v 26.5, p=0.003). Moreover, there was a trend in increasing levels of expression and significance of difference between normal tissue and carcinoma tissue with increasing Dukes stage (A p=.52, B p=0.03, C p=0.03) , T-Stage (1 p=1.0, 2 p=0.69, 3 p=0.04, 4 p=0.03), Nodal status (−ve p=0.07, +ve p=0.04 and tumour differentiation (well diff p=0.91, Mod. Diff p= 0.06, Poor. Diff. p= 0.026). Conclusions: COM-1 expression is increased in colorectal tumour tissues when compared to normal mucosa. This is reflected at both the protein and mRNA levels within the cells. In addition there is evidence of dislocated expression and redistribution of COM-1 protein with normal protein expression remaining intra-nuclear however, in tumours COM-1 then becomes cytoplasmic. Aberant over-expression of COM-1 has been identified in other human carcinoma types and has been linked with advanced disease, here we have demonstrated a similar pattern in colorectal carcinomas. No significant financial relationships to disclose.
Validation of an RT-PCR multi-gene prognostic signature for distant metastasis in node negative (N-), ER positive (ER+) breast cancer patients using FFPE sections
Authors: Tutt A. , Wang A. , Springall R. , Lau K. , Ryder K. , Kam Morgan L. , Broder S. , Esserman L. , Gillett C. , Sninsky J. 
Published: March 2020

21009 Background: We sought to validate a previously developed 14-gene prognostic signature and a metastasis score (MS) that predicted distant metastasis in N-, ER+ breast cancer patients in an independent sample set of patients without systemic treatment. The genes consisted primarily of proliferation genes involved in p53 and TNF signaling pathways. Methods: : A cohort of 294 N-, ER+ breast cancer patients from Guy's Hospitals, London, UK without systemic therapy were tested. The cohort had a mean age of 55.5 yrs with 49% > 55 yrs, mean tumor size of 1.93 (max. 3) cm, and a median follow up of 14.3 yrs. The primary endpoint was distant metastasis free survival. RT-PCR was carried out on fixed sections. The MS was calculated. Results: The mean MS (SD) was 0.44 (0.59) with a range of -1.31 to 2.0. Hazard of distant metastasis increased 3.02 fold (95% CI 1.91–4.76, p <0.0001) per unit increase in MS from Cox model. The pre-determined cut point of zero was used to stratify patients into low- and high-risk groups. The 5-yr distant-metastasis-free survival rate (DMFSR) for low- and high-risk groups were 1 and 0.86 (SE 0.024); the 10-yr DMFSR were 0.97 (0.021) and 0.77 (0.030), respectively. Univariate Cox regression analyses indicated that MS (hazard ratio (HR) 5.65, 95% CI 2.05–15.56, p=0.008), tumor size (HR 1.62, p=0.0047) and tumor grade (HR 2.52, p=0.036) were significant but age was not. Multivariate Cox regression indicated that the signature had independent prognostic value with a HR of 4.71 (1.42–15.61, p=0.011) after adjusting for age, tumor size and grade. AUC of MS at 5-and 10-yr were 0.78 (0.71–0.85, p<0.001) and 0.73 (0.66–0.80, p<0.001) with sensitivities of 1 and 0.96 and specificities of 0.31 and 0.31 at zero cut point, respectively. The differential risk between the median MS scores of the lowest and highest deciles was 8-fold. Conclusions: A previously defined RT-PCR prognostic signature for N-, ER+ patients has been confirmed. A metastasis score that quantifies distant metastasis risk, not confounded with treatment effect can complement treatment response predictors. Insight on natural history of tumors is critical for evaluating impact of therapy. No significant financial relationships to disclose.
Identification of epigenetic aberrant promoter methylation of RASSF1A in serum DNA and its clinicopathological significance in lung cancer
Authors: Chen L. , Wang Y. , Yu Z. 
Published: March 2020

21014 Objective: To detect the hypermethylation status of RASSF1A promoter in serum DNA of lung cancer patients and to analyze its correlation with clinicopathological features. Methods: Serum DNA was extracted from peripheral blood from 80 primary lung cancer patients, 35 benign pulmonary disease patients and 15 healthy donors. The methylation status of RASSF1A promoter was determined using methylation-specific PCR technique, and the correlation between methylation profiles and clinicopathological parameters was statistically analyzed. Results: Aberrant methylation of RASSF1A was detected in 27 of the 80 (33.8%) patients with lung cancer but no benign pulmonary disease patients or healthy donors (p<0.001). RASSF1A was preferentially observed in small cell lung cancer (p=0.042), while no statistical difference was found among methylation frequencies of different subtypes of non-small cell lung cancer. The methylation status was also found to be associated with relative poor differentiation (p=0.009) and late stage (p=0.013), but not with gender, age or treatment. Conclusion: RASSF1A promoter is frequently hypermethylated in serum DNA of primary lung cancer patients, and RASSF1A is a promising novel biomarker for lung cancer diagnosis. No significant financial relationships to disclose.
Lymph node metastasis in breast cancer: The role of tumor markers
Authors: Lund M. J. , Graham S. M. , Liff J. M. , Coates R. J. , Flagg E. W. , Yuan X. , Lin M. G. , Eley J. W. , Porter P. L. 
Published: March 2020

21019 Background: Women diagnosed with lymph node positive breast cancer have a greater chance of recurrence and death than women with lymph node negative disease. Tumor markers are becoming increasingly important to understanding breast cancer progression, yet little is known about their relationship with lymph node status. The purpose of this study is to examine whether prognostic and novel cell-cycle tumor markers are associated with lymph node status in black and white women with invasive breast cancer. Methods: This study included 202 lymph node positive and 292 node negative women, ages 20–54 years, diagnosed with invasive breast cancer between 1990 and 1992, and previously enrolled in a population-based study in Atlanta, Georgia. Tumor specimens were centrally reviewed and evaluated for lymphovascular invasion (LVI) and Nottingham tumor grade. Expression of estrogen and progesterone receptors (ER and PR), c-ErbB-2, Ki-67, pRb, p16, p21, p27, p130/Rb2, p53, cyclin E, and cyclin D1 were centrally assayed by immunohistochemistry. Relationships between each tumor marker and lymph node status were assessed by logistic regression, after adjusting for prognostic and socio-demographic factors. Results: Several tumor markers were associated with lymph node status, but differed by tumor size. Among women with smaller tumors (≤2.0 cm), p130 (OR=0.6, 95% CI 0.4–1.0), Bcl-2 (OR=0.4, 95% CI 0.2–0.8), and cyclin D1 (OR=1.7, 95% CI 1.0–2.8) were significant predictors of positive lymph node status. Among women with tumors > 2.0 cm, p53 (OR=0.5, 95% CI 0.3–0.8), and cyclin E (OR=0.4, 95% CI 0.2–0.9), and pRb (OR=1.6, (95% CI 1.0–2.6) were significant predictors. Black women with smaller tumors were 50% more likely to have lymph node metastasis. LVI and high grade remained the strongest predictors of lymph node metastasis in all regression models. Conclusions: Our findings suggest that there may be a different mechanism for lymph node spread in aggressive smaller tumors compared to larger tumors. Identifying markers for aggressive tumors could lead to the benefit of more effective treatment, particularly among black women for whom race may be a surrogate for other markers not accounted for in our study. No significant financial relationships to disclose.
Preferential chemosensitivity to gemcitabine by cyclin E overexpression in human gastric cancers
Authors: Yeh K. , Shen Y. , Chiang Y. , Liu P. , Huang C. , Cheng A. 
Published: March 2020

21020 Background: Exploration of molecular determinants for chemosensitivity is the key element of personalized cancer therapy. Cyclin E is a major G1-phase cyclin, together with the CDK2, which mediates phosphorylation and functional inactivation of Rb protein. Cyclin E overexpression has been demonstrated in a variety of cancers, including human gastric cancers (GC), while its biologic significance in drug therapy remains unclear. Previously, we have demonstrated that cyclin D1 overexpression plays an important role in differential chemosensitivity of human GC cells (Proc Am Assoc Cancer Res 2004; 45: abstract 4888). In this study, we examine the roles between cyclin E overexpression and chemosensitivity of human GC cells. Methods: Compared human gastric cancer cells (NCI-N87) with stably transfected cells (N87-CyE), which have 2-fold overexpression of cyclin E, the IC50 for gemcitabine (2'-2'-difluoro- deoxycytidine, dFdC) was more than 1-log lower in N87-CyE (17.0 ± 2.7 nM) than N87 cells (113.7 ± 6.5 nM) by MTT colorimetric cytotoxicity assay. In contrast, the N87-CyE cells are only slightly more chemosensitive to taxanes (paclitaxel and docetaxel), and confer largely identical chemosensitivity to 5-FU, cisplatin, and irinotecan (CPT-11). We applied RNA interference (RNAi) of cyclin E to N87 cells. The stably transfected N87-CyE/RNAi cells readily confer gemcitabine resistance with the IC50 for gemcitabine of 124.5 ± 1.6 nM. Results: Gemcitabine-induced apoptosis in N87, N87-CyE, or N87-CyE/RNAi cells was shown in either caspase-3 or PARP (poly ADP-ribose polymerase) cleavage assay by Western blotting, and Annexin-V-FITC apoptosis detection by flowcytometry. The threshold concentration of gemcitabine for caspase-3 and PARP cleavage was 10–25 nM for N87-CyE, and 100–200 nM for N87 or N87-CyE/RNAi, respectively. Conclusions: Our data demonstrate that preferential chemosensitivity to gemcitabine by cyclin E overexpression in gastric cancer cells. Gemcitabine-induced apoptosis is enhanced by cyclin E overexpression, while is reduced by RNAi of cyclin E. Further studies for potential clinical use of gemcitabine in personalized chemotherapy for cyclin E or cyclin D1-overexpressing GC are warranted (supported by the grants of NHRI-CN-CA9201S, Taiwan). No significant financial relationships to disclose.
Relationship of angiogenesis biomarkers and clinical response to bevacizumab (Bev) in persistent or recurrent epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) patients treated in a Phase II Gynecologic Oncology Group study
Authors: Han E. S. , Burger R. A. , Randall-Whitis L. , Parmakhtiar B. , Darcy K. , Sill M. , Connelly P. , Monk B. J. , Fruehauf J. P. 
Published: March 2020

21021 Background: Angiogenesis promotes tumor growth and is associated with poor outcomes in ovarian cancer. Currently, there are no markers to predict or determine response to anti-angiogenesis therapies. Methods: Persistent or recurrent EOC/PPC patients (1–2 prior cytotoxic regimens, measurable disease, and GOG performance status = 2) were treated with Bev (15mg/kg IV q21days) until progression. Tissue biopsies, serum samples and dynamic contrast enhanced MRIs (DC-MRI) were obtained prior to initiation (PT01) and 4th cycle (PT02) of Bev therapy. Tumor vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), and mutant p53 were determined by immunohistochemistry (IHC) and scored using histoscore (HS) analysis ([1 + staining score (0 to 4)] x % positive). Microvessel density (MVD) was determined by counting CD31 IHC hot spots. Serum VEGF levels were obtained by ELISA. Variables were considered as continuous or discontinuous in this training set to establish appropriate cut points to be applied to an ongoing phase III trial (GOG218). Results: From 4/02 to 8/04, 62 eligible patients were enrolled. A 17.7% response rate with 40% of patients with no evidence of disease progression for at least 6 months was previously reported (ASCO 2005). 44 tissue samples from PT01 and 27 from PT02 were evaluable for IHC biomarker levels. Based on current analysis, VEGF HS average was 92 at low MVD counts, while at high MVD counts, VEGF HS average was higher at 159 (p=0.06). In addition, 77% of TSP-1 negative tissues were VEGF positive, while 52% of TSP-1 positive tissues were VEGF positive. Analysis of serum VEGF levels (from 56 PT01 and 39 PT02 specimens) and DCMRIs (49 PT01 and 42 PT02 MRIs) are ongoing. Conclusions: Higher tumorVEGF was associated with increased angiogenesis and lower TSP-1 tissue levels. Results from the biomarkers tested await correlation to the mature survival data which should be available by June 2007. We plan to determine whether an angiogenesis biomarker profile is associated with patient response to Bev therapy. No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) as a potential new target in the treatment of patients with adrenocortical carcinoma: Results of pre-clinical studies
Authors: Fassnacht M. , Hahner S. , Adam P. , Heinrich B. , Quinkler M. , Stroebel P. , Allolio B. 
Published: March 2020

21025 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with incompletely understood pathogenesis and poor prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been demonstrated in several tumors and is partly associated with a more aggressive phenotype and a worse prognosis. In addition, targeting the EGFR tyrosine kinase represents a successful new therapeutic strategy, e.g. in non-small cell lung cancer. Therefore, we investigated the role of EGFR in ACC as a potential therapeutic target. Methods: EGFR expression was analyzed by immunohistochemistry in 115 ACCs and 5 normal adrenals using paraffin sections and tissue arrays (scoring of expression: 0–3). Utilizing the clinical data from the German ACC registry, Kaplan Meier survival analyses were performed. In 30 patients the tumor DNA was sequenced for mutations of the “hot spot” exons 19–21 of the EGFR gene. In addition, cells of the ACC cell line NCI-h295 were incubated with the EGFR antibody cetuximab (1–100 μg/ml) and cell proliferation was measured by MTT tests. Results: Immunohistochemistry revealed EGFR expression in 78% of ACCs. In 67/115 (58%) of the ACCs and 0/5 of the normal adrenals the expression level was judged as moderate-to-high (score 2 or 3). However, the expression level did not correlate with the clinical outcome in these patients. In addition, none of the sequenced tumor DNA samples showed a mutation in exons 19–21. Cetuximab exhibited a dose dependent antiproliferative effect in NCI-H295 cells (cell viability: 1μg/ml: 95±2%; 10μg/ml 90±3%*; 100 μg/ml 85±4%* vs untreated control cells: 100±3%; * = p<0.01). Conclusion: EGFR is overexpressed in the majority of ACC. Moreover, in vitro experiments demonstrated that inhibition of EGFR signalling lead to moderate growth inhibition in ACC cells. Therefore, in patients with ACC refractory to established cytotoxic therapies the experimental use of EGFR inhibitors (combined with cytotoxic therapy) seems to be justified. No significant financial relationships to disclose.
Immune signatures hold prognostic import across solids tumors
Authors: Hsu S. D. , Anders C. K. , Acharya C. R. , Zhang Y. , Wang Y. , Foekens J. A. , Blackwell K. L. , Drake C. G. , Morse M. A. , Febbo P. G. 
Published: March 2020

21041 Background: The host immune response can impact cancer growth, prognosis, and response to therapy. In colorectal cancer, the presence of cells involved with T-cell mediated adaptive immunity better predicts of survival than the current staging method. Immune signatures based on host response to cancer have the potential to predict prognosis and facilitate target specific therapy. Methods: We used the gene expression data associated with immune host response to colorectal cancer (Galon et al., Science 2006) to perform hierarchical clustering of solid tumors for which the clinical annotation were available. Specifically, prostate (n=79), breast (n=132), lung (n=37), and lymphoma (n=127) samples were clustered based upon expression of genes associated with host immune responses (Th1 mediated adaptive immunity (Th1), inflammation, and immune suppression (IS)). Kaplan-Meier survival analysis was then used to determine if major sample clusters had significantly different disease free survival. Results: Clusters with differential prognosis (disease free survival) were consistently seen across all tumors. Among adenocarcinomas, and similar to previously published colorectal data, the Th1 genes were consistently associated with better prognosis. Specifically, in breast cancer patients, increased expression of the Th1 genes was protective, but only in patients under 45 years of age (HR=0.42; p=0.05). In prostate cancer, patients with increased expression of the Th1 genes and inflammation genes had better prognosis when compared to those without the Th1 genes (HR=0.36; p=0.03) or inflammation genes (HR=0.37; p=0.03). Lung cancer patients expressing the Th1 genes and IS genes appear to have improved survival when compared to those without the IS genes (HR=0.33; p=0.08). In contrast, Th1 genes were associated with poorer prognosis in lymphoma patients. Patients with decreased Th1 genes and increased expression of inflammation genes had better prognosis than those expressing the Th1 genes (HR=0.43; p=0.013) or IS genes (HR= 0.35; p=0.002) only. Conclusions: Signatures of the host immune response to solid tumors hold prognostic significance. Future work will determine if immune signatures can be predictive of response to therapy and help guide management. No significant financial relationships to disclose.
Oncolytic adenovirus expressing apoptotic genes targets radiation resistant (RR) esophageal cancer
Authors: Chang J. Y. , Komaki R. , Zhang X. , Wang L. , Fang B. 
Published: March 2020

21043 Background: Only 25% of esophageal cancer patients achieve pathological complete response after standard chemoradiotherapy. Radiation dose escalation is associated with higher toxicity but no therapeutic improvement. In addition, esophageal cancer cells may develop radiation resistance (RR) after fractionated radiation exposure. Therefore, molecular targeting therapy for RR esophageal cancer is urgently needed. Methods: Six pairs of RR esophageal cancer cell lines were established by applying continuous 2 Gy fractionated irradiation. Ad/TRAIL-E1, an oncolytic adenoviral vector expressing both apoptotic TRAIL and viral E1A genes under the control of tumor specific human telomerase reverse transcriptase promoter, was constructed. Phosphate buffer solution and vectors expressing the TRAIL gene only, the GFP marker protein only, or the E1A gene only served as controls. Trans-gene expression, apoptosis activation, and the RR esophageal cancer cells targeted were evaluated in vitro and in vivo. A human esophageal RR cancer model was established and locally treated with Ad/TRAIL-E1 or controls. Results: After fractionated radiation exposure, esophageal cancer cell lines developed RR (up to 25-fold) that was associated with activation of the anti-apoptotic pathway. Ad/TRAIL-E1 activated an apoptotic cascade of caspases and selectively killed esophageal cancer cells but not normal cells. Ad/TRAIL-E1 preferentially targeted RR stem-like cancer cells with higher trans-gene expression and cell killing compared with parental cells. Overexpression (3 times) of Coxsackie's and adenoviral receptors in RR esophageal cancer cells compared with parental cells was noted. Ad/TRAIL-E1 therapy resulted in 40% tumor-free survival without the treatment- related toxicity found in human RR esophageal adenocarcinoma mouse models (p<0.05 as compared with controls). Conclusions: Esophageal cancer cells develop RR after fractionated radiation exposure. Ad/TRAIL-E1 preferentially targeted RR stem-like esophageal cancer cells, which resulted in a 40% cure rate. No significant financial relationships to disclose.