bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3388: Genetic prediction of VEGF-A plasma levels in cancer patients
Authors: Innocenti Federico , Jiang Chen , Sibley Alexander , Etheridge Amy , Furukawa Yoichi , Kubo Michiaki , Kindler Hedy L. , Venook Alan P. , Hurwitz Herber I. , Nixon Andrew B. , Owzar Kouros 
Published: July 2016

Abstract
ABSTRACT
Background: Angiogenesis is an essential event in tumor growth, progression and metastasis and is strongly regulated by multiple VEGF ligands and receptors. We sought to discover genetic variants that could predict levels of circulating angiogenic proteins in cancer patients prior to receiving therapy.
Methods: EDTA plasma was collected at baseline (before treatment) in 216 treatment naïve pancreatic cancer patients (CALGB 80303, discovery) and 149 treatment naïve colorectal cancer patients (CALGB 80203, validation). Thirty-one angiogenic factors were measured by a multiplexed ELISA assay. Genetic variants associated with levels of each of the 31 proteins were selected from a genome-wide genotyping of 484,523 common variants in CALGB 80303. Using a cut off of p&lt;10−8 for association, variants were selected from CALGB 80303, genotyped in CALGB 80203 and associations tested with the same protein levels. The Jonckheere-Terpstra test was used. Additionally, mRNA was extracted from formalin-fixed, paraffin-embedded primary tumors from patients in CALGB 80203 and tissue levels of VEGF-A analyzed by RT-PCR.
Results: In CALGB 80303, three genetic variants passed the p&lt;10−8 cut off for significance: rs2284284 for MCP1, rs7504372 for VEGFC, and rs7767396 for VEFG-A levels. Of these, only rs7767396 (A&gt;G) for VEFG-A levels was validated in CALGB 80203 (p = 1.23×10−5). Patients with the AA genotype exhibited 2.2-fold higher VEGF-A levels than AG patients, who had 1.2-fold higher levels than GG patients. rs7767396 was not associated with VEGF-A mRNA levels from the primary tumors of patients in CALGB 80203 (p&gt;0.05). rs7767396 is a common variant (frequency of 49% in Europeans), is located about 150 Kb 3’ to the VEGFA gene, and is predicted by HaploReg to disrupt the binding motifs of two transcription factors, NF-AT1 and ZBRK1.
Conclusions: A common genetic variant predicts the levels of circulating VEGF-A in cancer patients. A similar effect has been also shown in non-cancerous individuals (Debette S et al., Circ Res, 2011). Due to the central role of VEFG-A in the pathophysiology of many conditions, genetic testing could predict patients who have high versus low levels, potentially helping to guide the use of anti-angiogenesis therapies.
Citation Format: Federico Innocenti, Chen Jiang, Alexander Sibley, Amy Etheridge, Yoichi Furukawa, Michiaki Kubo, Hedy L. Kindler, Alan P. Venook, Herber I. Hurwitz, Andrew B. Nixon, Kouros Owzar. Genetic prediction of VEGF-A plasma levels in cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3388.
Abstract 3391: SCUBE2 is a co-receptor for VEGFR2 in tumor angiogenesis
Authors: Lin Yuh-Charn , Yang Ruey-Bing 
Published: July 2016

Abstract
Signal peptide-complement protein C1r/C1s, Uegf, and Bmp1 (CUB)-epidermal growth factor (EGF) domain-containing protein 2 (SCUBE2) is a peripheral membrane protein expressed in normal tissue and tumor vascular endothelial cells (ECs); however, its role in angiogenesis remains poorly understood. In this study, we show that endothelial SCUBE2 is upregulated by hypoxia and acts as a co-receptor for VEGFR2 to facilitate VEGF binding to VEGFR2 and augment its signals including VEGFR2 phosphorylation and p44/42 MAPKs/Akt activation, thus promotes cell proliferation and tubule formation in ECs. While physiological angiogenesis remained normal in the endothelial ablation of Scube2 in mice, pathological angiogenesis in experimental tumors was altered, resulting in smaller tumors and reduced microvascular density. To simulate the angiogenic environment of the tumor, Scube2-deficient ECs were isolated and propagated in vitro with VEGF. Mutant ECs exhibited marked reduction in binding of VEGF, proliferation and sprouting responses to VEGF as well as downstream signal activation. Our results reveal that SCUBE2 might act as a novel co-receptor for VEGFR2, and point that targeting such SCUBE2 function in human ECs may represent a potential anti-tumor strategy by inhibiting tumor angiogenesis.
Citation Format: Yuh-Charn Lin, Ruey-Bing Yang. SCUBE2 is a co-receptor for VEGFR2 in tumor angiogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3391.
Abstract 3394: Bevacizumab enhances the antitumor effect of BRAFV600E inhibition in colorectal and melanoma xenograft models
Authors: Comunanza Valentina , Corà Davide , Middonti Emanuele , Di Nicolantonio Federica , Medico Enzo , Sangiolo Dario , Bussolino Federico 
Published: July 2016

Abstract
BRAF inhibitors (BRAFi) have shown improved response rate and overall survival (OS) compared to standard chemotherapy in metastatic melanoma. Combinations of BRAF and MEK targeted agents further improve progression-free survival (PFS) and OS when compared with single-agent BRAFi, but the development of resistance remains a major obstacle to long-term disease control. Thus, additional strategies must be exploited to increase the efficacy of BRAF-MEK blockade in metastatic melanoma and circumvent or delay the onset of resistance.
We have previously demonstrated in murine xenograft models of BRAF mutant melanomas and colorectal cancers (CRC) that the vemurafenib analog, PLX4720, has cytostatic activity and induces vascular normalization by changing the pro-angiogenic program triggered by the oncogenic mutation (Bottos A et al., 2012;109(6):E353-9). We hypothesized that BRAF-targeted inhibitors could cooperate with anti-angiogenic regimens in the treatment of BRAF-mutant melanoma and colorectal tumors.
Here, we demonstrated that when associated with the VEGFA neutralizing antibody bevacizumab (COMBO), PLX4720 shows enhanced anti-cancer effects and induces a de novo transcriptional signature in BRAF mutant melanoma and colorectal xenografts. Interestingly, in the COMBO, bevacizumab does not alter the improvement in blood perfusion and tumor vessel normalization observed with PLX4720 alone. Although targeted inhibition of either BRAF or VEGFA initially suppresses the tumor growth, only combined inhibition of both pathways results in an evident apoptotic effect. Furthermore, bevacizumab delays the onset of resistance to PLX4720 by recruiting macrophages with a M1-like phenotype and inducing a remodeling of the extracellular matrix. The latter is characterized by a reduction in collagen deposition and of cancer-associated fibroblasts (CAFs), known to sustain cancer progression. The effect of bevacizumab on acquired resistance to PLX4720 is transient and depends on the presence of M1 macrophages. Indeed, 3/6 xenografts treated with COMBO start re-growing after 6 weeks with a dramatic reduction of infiltrating macrophages and an increase of CAFs.
Collectively, our findings offer a new perspective for the management of clinical resistance to BRAF inhibitors and offer a rationale to combine BRAFV600E inhibitors with anti-angiogenic regimens.
Citation Format: Valentina Comunanza, Davide Corà, Emanuele Middonti, Federica Di Nicolantonio, Enzo Medico, Dario Sangiolo, Federico Bussolino. Bevacizumab enhances the antitumor effect of BRAFV600E inhibition in colorectal and melanoma xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3394.
Abstract 3409: Nonsynonymous functional variants in DNA repair genes in sporadic colorectal cancer: searching for predictive and prognostic markers
Authors: Jiraskova Katerina , Slyskova Jana , Rosa Fabio , Di Gaetano Cornelia , Pardini Barbara , Vymetalkova Veronika , Vodicka Pavel 
Published: July 2016

Abstract
Colorectal cancer (CRC) has one of the highest mortality due to the late diagnosis and a lack of proper predictive and prognostic markers. According to the current knowledge, DNA repair processes are involved both in the onset of CRC and in the treatment efficacy.
In the present study, we analyzed the link between functional genetic polymorphisms (SNPs) in DNA repair genes covering the main DNA repair pathways (relevant for therapy response) in relation with the risk of CRC and clinical outcomes. Our set of candidate polymorphisms was selected according to different functional and genomic databases (FSNP, GAD, Linkage Disequilibrium, Gerp++, SiPhy). FSNP database provides integrated information about the functional effects of SNPs which are predicted and indicated at several levels (protein coding, splicing regulation, transcriptional regulation, post translation). We have focused on those affecting protein coding. We hypothesize that these modified proteins modulate the function/efficiency of DNA repair, and thus may have an effect on CRC.
Sixteen polymorphisms in twelve DNA repair genes (C19orf40, EME1, FANCI, MUS81, NEIL3, POLE, POLN, POLQ, RAD51D, REV1, REV3L, RPA1) were analyzed in DNA samples of 1080 cases and 1442 controls from the Czech Republic. Clinical data at diagnosis and complete information on follow up were provided for all patients.
Genetic variations in several DNA repair genes were associated with clinical outcome. In particular, CRC patients carrying the AG heterozygous genotype for rs5030755 in RPA1 gene displayed a longer survival and decreased recurrence risk (Overall Survival (OS): HR 0.74; 95% CI 0.56-0.98; p = 0.04 and Event-Free Survival (EFS): HR 0.72; 95% CI 0.54-0.95; p = 0.02). This association with better OS was more pronounced in individuals with colon and sigmoideum cancer (HR 0.58; 95% CI 0.4-0.83; p = 0.0035).
Understanding the SNPs effect on the treatment response, resulting ultimately into low-cost and low-invasive markers, is regarded as very important for the possibility to tailor patient specific treatment strategy. Individualized therapy will eventually help to improve therapeutic efficacy and to minimize toxicities. The present results identified plausible candidate DNA repair gene variants potentially affecting clinical outcome in relation to CRC patient's survival.
Supported by grant GA UK 112515, GA CR 15-14789S
Citation Format: Katerina Jiraskova, Jana Slyskova, Fabio Rosa, Cornelia Di Gaetano, Barbara Pardini, Veronika Vymetalkova, Pavel Vodicka. Nonsynonymous functional variants in DNA repair genes in sporadic colorectal cancer: searching for predictive and prognostic markers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3409.
Abstract 3417: Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy
Authors: Song Qingkun , Ren Jun , Yu Jing , Wang Xiaoli , Zhou Xinna , Lyerly Herbert Kim 
Published: July 2016

Abstract
Introduction: This study aimed to assess the prognostic value of CD8+CD28− T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy.
Methods: 217 patients participated in the follow-up study. CD8+CD28− proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD8+CD28− proportion more than 24.2% and less than or equal to 24.2% in peripheral T cells.
Results
The median follow-up period was 15 months. Median time to progression was 11.8 months among patients with CD8+CD28− proportion less than or equal to 24.2% and 7.1 months among patients with CD8+CD28− proportion more than 24.2% (p&lt;0.05). With further adjustments, CD8+CD28− proportion of more than 24.2% produced a HR being 2.13 (95%CI 1.45, 3.12) for progression. Patients with CD8+CD28− proportion of less than or equal to 24.2% had median overall survival of 36.2 months, 10.6-month longer than patients with higher CD8+CD28− proportion (p&lt;0.05). With further adjustments, CD8+CD28− proportion of more than 24.2% produced a 86% higher risk for death (HR = 1.86, 95%CI 1.07, 3.24).
Conclusion
Peripheral CD8+CD28− proportion had a negative association with progression-free and overall survival among breast cancer patients receiving adoptive T cell immunotherapy. CD8+CD28− suppressive T cell was a potential biomarker for breast cancer patients’ prognosis.
Citation Format: Qingkun Song, Jun Ren, Jing Yu, Xiaoli Wang, Xinna Zhou, Herbert Kim Lyerly. Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3417.
Abstract 3418: Differential prognostic effect of smoking and multivitamin use on lung cancer survival by sex
Authors: Yang Mi , Oh Hyun-Kyung , Shim Young Mog , Shin Myung-Hee 
Published: July 2016

Abstract
Incidence of lung cancer is decreasing among men and increasing among women in developed countries and also in Korea. However, mortality of lung cancer is still the highest among male cancers. Smoking is one of the group 1 carcinogens for lung cancer development, but its prognostic effect on lung cancer survival is not well established. Beta-carotene supplement increased the risk of lung cancer among smokers but the role of multivitamin supplement on the risk and survival of lung cancer is unclear either. We aimed to evaluate the association between smoking and multivitamin use on lung cancer survival by sex. We interviewed 910 pathologically confirmed lung cancer patients who were diagnosed between 2010 and 2012 in Samsung Medical Center. Questionnaire included current smoking status, age at first smoking, daily smoking amount, alcohol intake, past medical history, and multivitamin use. Pathological type, stage, and treatment information was collected from the electronic medical records. We followed the patients until December 31, 2012. Hazard Ratios (HR) and 95% Confidence Intervals (CI) were estimated using Cox's proportional hazard model (SAS9.4). We found significant difference in age at diagnosis, pathological type and stage between male and female patients; Female patients were younger, smoked less, used more multivitamin, and had more adenocarcinoma and earlier stage cancer than male patients. Smoking increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for those who smoked more than 40 pack-years compared to those who never smoked was 5.64 (95%CI = 1.43, 22.28) in women and 1.17 (95%CI = 0.61, 2.26) in men (p-interaction = 0.01) when adjusted for age, stage, and pathologic type. Multivitamin use also increased the risk of lung cancer mortality among female patients only. HR for lung cancer mortality for multivitamin users was 4.14(95%CI = 1.77, 9.73) in women and 1.46 (95%CI = 0.71, 3.00) in men (p-interaction = 0.17). The association between multivitamin use and lung cancer mortality was strongest among female non-smokers (HR = 4.10, 95%CI = 1.72, 9.77). In conclusion, smoking and multivitamin use worsen the survival of female lung cancer. Prognostic effect of multivitamin use may be stronger among non-smokers.
Citation Format: Mi Yang, Hyun-Kyung Oh, Young Mog Shim, Myung-Hee Shin. Differential prognostic effect of smoking and multivitamin use on lung cancer survival by sex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3418.
Abstract 3420: Clinical prognostic factors in adult with astrocytoma: Historic cohort
Authors: Wegman-Ostrosky Talia , Reynoso Noverón Nancy , Iliana Mejía-Pérez Sonia , Estefania Sánchez-Correa MD Thalía , María Álvarez Rosa , Cacho Bernardo , Montalvo Luis A. , Corona Teresita 
Published: July 2016

Abstract
Introduction: Malignant tumors of the central nervous system contribute extremely to cancer mortality especially in the high risk age groups. In USA are the second and the fifth leading cause of cancer mortality in men and women aged 20 to 39 years respectively. Astrocytomas are the most common and lethal tumors of the CNS, being the most common grade IV (glioblastoma) (4.37 per 100,000 population).
The prognosis of astrocytomas can be predicted by specific clinical factors allowing neurosurgeons and neuro-oncologists to define the best treatment for each patient. Some patients’ features like age, gender, performance status and tumor localization have been studied as potential prognostic factors. In Mexico there are few reports on demographic, clinical characteristics and prognostic factors in adults.
Objective: To explore the clinical prognostic factors for adults affected with astrocytoma
Methods: Using a historic cohort, we selected by simple randomization, 155 clinical files from patients with astrocytoma. The main outcome variable was overall survival time (OS). To identify clinical prognosis factors we used: bivariate analysis, Cox regression models, log rank test and Kaplan-Meier survival function.
Results: The mean age at diagnosis was 45.7 years. Compared with other studies, our population was 15 years younger when diagnosed. Analysis by stage in grade II, III and IV also showed a younger age of presentation. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. Kaplan-Meier survival estimate showed that the variables grade, Karnofsky Performance Status (KPS)&gt;70, the type of resection, chemotherapy, radiotherapy, alcohol consumption, familiar history of cancer and clinical presentation were significantly associated to survival time. Using proportional Hazard Model the variables: age, grade IV, resection, chemotherapy + radiotherapy and KPS where prognosis factors.
Conclusion: Astrocytoma in our study was present in young adults. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. The variables alcoholism, family history of cancer and clinical presentation influenced significantly survival time, and showed a tendency in the mortality analyses.
Citation Format: Talia Wegman-Ostrosky, Nancy Reynoso Noverón, Sonia Iliana Mejía-Pérez, Thalía Estefania Sánchez-Correa MD, Rosa María Álvarez, Bernardo Cacho, Luis A. Montalvo, Teresita Corona. Clinical prognostic factors in adult with astrocytoma: Historic cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3420.
Abstract 3422: The influence of genetic and clinical factors on the outcome following a diagnosis of small cell carcinoma of the ovary, hypercalcemic type
Authors: Witkowski Leora , Goudie Catherine , Ramos Pilar , Karnezis Anthony N. , Boshari Talia , Pautier Patricia , Longy Michel , Knost James A. , Saloustros Emmanouil , McCluggage W Glenn , Hasselblatt Martin , Hendricks William P. , Huntsman David , Levine Douglas A. , Trent Jeffrey , Foulkes William D. 
Published: July 2016

Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian tumor diagnosed in women below the age of 40. While it is uncommon, with only ∼500 cases reported, it is an extremely aggressive tumor, with long term survival rates of &lt;30% in early stage disease. Recently, we discovered that SCCOHT is a monogenic disease, attributable to germline and somatic deleterious mutations in the chromatin remodeling gene, SMARCA4. Since then, single case reports have been published on women affected with SCCOHT, but no large studies have been conducted on the effect of these mutations, germline or somatic, on the disease. Furthermore, while numerous publications have described the therapies used in single cases or small cohorts of SCCOHT patients, treatment remains varied, with no standardized protocols. In an attempt to clarify which factors have an effect on the course of the disease, we reviewed all published and a cohort of unpublished SCCOHT cases and collected information on the following factors: stage at diagnosis, age at diagnosis, treatment modality used (chemotherapy/radiotherapy/high dose chemotherapy), mutation type (germline/somatic), and length of survival. We were able to acquire information in at least 2 of these parameters in 267 cases and performed multiple analyses. Clinically, we found that the greatest influence on patient outcome was related to stage at diagnosis (p &lt; 0.001) and treatment modality (p = 0.01), while age at diagnosis had no significant effect (p = 0.72). Molecularly, the presence of a germline mutation in the patient did not affect the age of onset (p = 0.86), nor did it have an effect on the length of survival of the patient (p = 0.63). Overall, this is the largest study conducted to date analyzing the influence of clinical factors on the outcome of patients diagnosed with SCCOHT, and is the first large study to analyze the effect of germline mutations on the outcome of these patients.
Citation Format: Leora Witkowski, Catherine Goudie, Pilar Ramos, Anthony N. Karnezis, Talia Boshari, Patricia Pautier, Michel Longy, James A. Knost, Emmanouil Saloustros, W Glenn McCluggage, Martin Hasselblatt, William P. Hendricks, David Huntsman, Douglas A. Levine, Jeffrey Trent, William D. Foulkes. The influence of genetic and clinical factors on the outcome following a diagnosis of small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3422.