bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 338: A novel small molecule inhibitor of the Notch transcription activation complex
Authors: Lehal Rajwinder , Frismantas Viktoras , Loubéry Sylvain , Reinmuller Viktoria , Turcatti Gerardo , Gonzalez-Gaitan Marcos , Bourquin Jean-Pierre , Radtke Freddy
Published: July 2016

NOTCH signaling is a developmental pathway known to play critical roles during embryonic development as well as for the regulation of self-renewing tissues. Aberrant activation of NOTCH signaling leads to deregulation of the self-renewal process resulting in sustained proliferation, evasion of cell death, loss of differentiation capacity, invasion and metastasis, all of which are hallmarks of cancer. Over activation of NOTCH in human cancers can be a consequence of over expression of NOTCH ligands/receptors, GOF mutations in NOTCH receptors as well as chromosomal translocations leading to constitutive activation of the pathway. Given the importance of Notch signaling in human cancers, several therapeutic approaches have been utilized to block NOTCH signaling. Two of these strategies are; a) the use of monoclonal blocking antibodies (Mabs) against NOTCH ligands and receptors and b) the use of small molecule γ-secretase inhibitors (GSIs). However, these approaches can only be effective if tumor cells express full-length ligand or receptor molecules. On the contrary, in human cancers harbouring NOTCH gene fusion due to chromosomal translocations, the use of Mabs and GSIs will have very limited clinical benefits. A third, yet not fully explored approach could be the blockage of NOTCH signalling by targeting the most downstream event in the NOTCH cascade i,e NOTCH transcriptional activation complex using small molecule inhibitors.

Here we report discovery and identification of a novel, orally-active small molecule inhibitor, named CB-103, of the NOTCH pathway that blocks NOTCH signaling by targeting the NOTCH transcriptional activation complex in the nucleus. CB-103 has shown the ability to block NOTCH signalling in human cancer cell lines, induce neurogenic phenotype in drosophila, induce muscle cell differentiation and inhibit NOTCH dependent cellular processes in mice. In addition, CB-103 exhibit anti-tumor efficacy in a xenograft model of human triple negative breast cancer resistant to GSIs and Mabs against NOTCH ligands/receptors. Furthermore, CB-103 has shown a remarkable activity in PDX models of human T-ALL harbouring activation of the NOTCH pathway. Additional studies are underway on several analogs of CB-103 to determine ADME/PK/PD profile and nominate a development candidate for further clinical development of this novel inhibitor of the NOTCH pathway.

Citation Format: Rajwinder Lehal, Viktoras Frismantas, Sylvain Loubéry, Viktoria Reinmuller, Gerardo Turcatti, Marcos Gonzalez-Gaitan, Jean-Pierre Bourquin, Freddy Radtke. A novel small molecule inhibitor of the Notch transcription activation complex. [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 338.
Abstract 3382: A physiological model of the tumor microenvironment for screening drug delivery systems
Authors: Tang Yuan , Soroush Fariborz , Deosarkar Sudhir , Wang Bin , Prabhakarpandian Balabhaskar , Kiani Mohammad
Published: July 2016

Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle's physico-chemical properties. Tumor microvasculature has many unique features including unusual transport characteristics, high interstitial pressure, and enhanced permeability and retention (EPR) effect. Current in vitro models of tumor drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. The objective of this study is to develop and characterize a synthetic 3D solid tumor - endothelium model in a novel microfluidic platform that mimics the tumor microenvironment observed in vivo.

The novel synthetic tumor model consists of a vascular network of tumor derived endothelial cells forming a complete lumen in communication with 3D solid tumors. Primary human breast tumor associated endothelial cells (HBTAECs) were co-cultured under physiological fluid flow conditions with 3D tumor cells from metastastic (MDA-MB-231) or non-metastatic (MCF-7) origins to study the effect of metastatic potential on the integrity of the adjacent endothelial cell lining. Extravasation of fluorescently labeled liposomes across the endothelium to the tumors was measured following HBTAECs treatment with normal media, tumor conditioned media (TCM), or TNF-α. Tight junction formation was characterized using ZO-1 immunostaining.

MDA-MB-231 cells quickly invaded into the vascular network from their primary culture location whereas MCF-7 cells rarely grew beyond the boundary of tumor origin. Permeability of liposomes across the endothelium was significantly higher with TCM treatment compared to both control and TNF-α treated cells (P < 0.01, one-way ANOVA). ZO-1 staining indicated strong tight junction formation when HBTAECs were treated with normal media as compared to TCM or TNF-α.

We have successfully established an in vitro 3D tumor - endothelial cell co-culture model in a novel microfluidic platform that closely mimics the tumor microenvironment in vivo. This system reproduces the tumor permeability and retention (EPR) effect on a chip. This realistic in vitro model can have great potential in applications such as cell-cell/cell-drug carrier interaction studies, drug delivery carrier screening, and drug efficacy testing.

Citation Format: Yuan Tang, Fariborz Soroush, Sudhir Deosarkar, Bin Wang, Balabhaskar Prabhakarpandian, Mohammad Kiani. A physiological model of the tumor microenvironment for screening drug delivery systems. [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 3382.
Abstract 3385: Identification of tumor endothelium-related genes in colorectal cancer
Authors: Yorozu Akira , Yamamoto Eiichiro , Maruyama Reo , Kai Masahiro , Nishidate Toshihiko , Furuhata Tomohisa , Sugai Tamotsu , Suzuki Hiromu
Published: July 2016

Background and Aims:

Angiogenesis is a hallmark of cancer development that has been considered an attractive therapeutic target. In this study, we aimed to unravel the molecular mechanism of tumor angiogenesis in colorectal cancer (CRC).

Materials and Methods:

We isolated endothelial and epithelial cells from surgically resected 14 human CRC tissues by using antibodies against endothelial (CD146) and epithelial markers (EpCAM). RNA sequencing was carried out using 3 pairs of normal and tumor endothelial cells. Expression of the genes was validated using quantitative RT-PCR, immunohistochemistry. Functions of a selected gene were carried analyzed by tumor conditioned medium (TCM) experiments, tube formation assay, gene expression microarray and cell cycle analysis.

Results:

Through RNA-seq analysis, we identified 18 genes, which were upregulated in the endothelial cells isolated from CRC tissues. We further validated the results by performing quantitative RT-PCR and immunohistochemical analysis in a larger series of clinical samples, and identified gene A as a novel candidate of the tumor endothelium-related gene. Expression of gene A was also upregulated in human umbilical vein endothelial cells (HUVECs) treated with TCM obtained from CRC cell lines. Knockdown of gene A in HUVECs suppressed in vitro tube formation and induced G1 cell cycle arrest. Microarray analysis revealed that gene A knockdown induced expression changes of approximately 300 genes in HUVECs, and gene ontology analysis showed that genes related to cell cycle or cell division were significantly enriched in the affected genes. To confirm our findings in vivo, we co-transplanted CRC cells with HUVECs into nude mice. We found that gene A knockdown in HUVECs resulted in reduced micro vessel formations in the xenograft tissues.

Conclusion:

We identified elevated expression of gene A in tumor endothelial cells of primary colorectal cancer tissues. Our results suggest that gene A may play an important role in the angiogenesis in colorectal cancer, and that it could be a potential therapeutic target.

Citation Format: Akira Yorozu, Eiichiro Yamamoto, Reo Maruyama, Masahiro Kai, Toshihiko Nishidate, Tomohisa Furuhata, Tamotsu Sugai, Hiromu Suzuki. Identification of tumor endothelium-related genes in colorectal cancer. [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 3385.
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

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<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<10−8 cut off for significance: rs2284284 for MCP1, rs7504372 for VEGFC, and rs7767396 for VEFG-A levels. Of these, only rs7767396 (A>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>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

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

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

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

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<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<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

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

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)>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

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 <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 < 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.
Abstract 3429: Evidence chronic inflammation is a risk factor for histiocytic sarcoma in Bernese mountain dogs - implications for human histiocytic sarcoma
Authors: Ruple-Czerniak Audrey , Morley Paul S.
Published: July 2016

The purpose of this study was to evaluate exposure variables associated with development of histiocytic sarcoma (HS), a rare but aggressive malignancy, using the canine spontaneous tumor model. The domestic dog has been shown to be an excellent model to investigate risk of occurrence of complex diseases in humans, especially cancers. This is due in part to the limited genetic heterogeneity within specific dog breeds. HS, though rare in most breeds of dogs, is a common malignancy in Bernese mountain dogs (BMD) with up to 25% of the population of dogs being diagnosed with HS during their lifetime. The frequency of HS diagnosis in BMDs is thought to be due to a heritable mutation in a single gene region analogous to the human chromosome 9p21. For this study, owners of BMDs registered with a non-profit breed registry, the Berner-Garde Foundation, were recruited for participation in an internet-based cross-sectional survey. Data were collected for a total of 216 BMDs. Of the total population of BMDs enrolled in the study 118 dogs were sibling-sets representing a case and a non-case that originated from the same litter. Mixed effects logistic regression (MELR) and conditional logistic regression (CLR) were used in parallel to examine associations between potential risk factors and the occurrence of HS. When controlling for litter of origin (as a marker of relatedness), dogs diagnosed with orthopedic conditions were found to be more likely to develop HS (MELR, OR: 2.5, 95% CI: 1.5, 5.2; CLR, OR: 2.81, 95% CI: 1.1, 7.3), while dogs receiving prescription anti-inflammatory medications were found to be at a considerably lower risk of developing this disease (MELR, OR: 0.43, 95% CI: 0.2, 0.8; CLR, OR: 0.32, 95% CI: 0.1, 0.8). These data suggest inflammation may be a modifiable risk factor for the development of HS. Therefore, identification and treatment of conditions that promote inflammatory mechanisms may reduce future risk of developing HS in dogs and people. Results of logistic regression models examining risk factors associated with development of histiocyRisk factorCategoryOdds ratio (MELR), n = 21695% CIP-ValueOdds ratio (CLR), n = 11895% CIP-ValueOrthopedic conditionYes2.491.21, 5.140.0142.811.08, 7.260.034NoReferenceReferenceNon-prescription medication useYes2.101.05, 4.180.0362.881.04, 7.900.041NoReferenceReferenceLong-term prescription medication useYes0.430.22, 0.810.0100.320.12, 0.830.020NoReferenceReference

Citation Format: Audrey Ruple-Czerniak, Paul S. Morley. Evidence chronic inflammation is a risk factor for histiocytic sarcoma in Bernese mountain dogs - implications for human histiocytic sarcoma. [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 3429.
Abstract 3433: Association between serum concentrations of polychlorinated biphenyls (PCBs) and increased risk of breast cancer among US women
Authors: Morgan Marisa , Deoraj Alok , Roy Deodutta
Published: July 2016

The main objective of this study was to examine the cross-sectional relationship between exposure to PCBs or their congeners and breast cancer among US women. There is limited information on the association of specific PCB congener or their combination levels in blood serum with increased breast cancer risk. PCBs are weak estrogens which has been shown to act as endocrine disrupters by increasing or blocking estrogen like activities in animals and humans. We analyzed National Health and Nutrition Examination Survey (NHANES) data from 1999-2004 in the lipid adjusted blood samples of female participants (>20 years of age). Exposure assessment was based on lipid adjusted serum levels of 6 individual PCB congeners (PCB 074, 099, 118, 138, 153, and 180), the sum of dioxin-like PCBs (074 and 118), and the sum of non-dioxin-like PCBs (099 + 138 + 153+187) in conjunction with data obtained from the medical and reproductive health questionnaires. We calculated geometric means to compare PCB concentrations in women's blood samples who also self-reported a breast cancer diagnosis and women who were never diagnosed with cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between PCB, their congener or their combinations and breast cancer. We evaluated age, race/ethnicity, age at menarche, body mass index (BMI; kg/m2), and lactation as potential confounders. Our results show a weighted geometric mean levels of 6 PCB congeners to be significantly higher in blood serum among women with breast cancer when compared to the rest of the study population. After adjusting for age, race, BMI, lactation, and age at menarche we found significant association of PCB 138 with breast cancer [odds ratios of 2.88; 95% confidence interval (CI): 1.14-7.30; 2.93, 95% CI: 1.04-8.26; and 3.43, 95% CI: 1.12-10.4] in women with higher body burdens of individual PCB congeners (> 50th percentile, 50th-75th percentile, and ≥75th percentile), respectively. After adjusting for age and race, it was also found that the sum of non-dioxin-like PCBs (074 and 118) in blood serum is significantly associated with breast cancer [OR of 1.14; 95% CI: 1.00-1.29]. In summary, our results suggest a possible link between environmental exposures to PCBs and increased risk of breast cancer among U.S. women.

Citation Format: Marisa Morgan, Alok Deoraj, Deodutta Roy. Association between serum concentrations of polychlorinated biphenyls (PCBs) and increased risk of breast cancer among US women. [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 3433.
Abstract 3444: Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population
Authors: Hang Dong , Yin Yin , Han Jing , Jiang Jie , Ma Hongxia , Xie Shuanghua , Feng Xiaoshuang , Zhang Kai , Hu Zhibin , Hongbing Shen , Clifford Gary M. , Dai Min , Li Ni
Published: July 2016

HPV16 is the most carcinogenic HPV type, but only a minority of HPV16 infections progress to cancer. Intratype genetic variants of HPV16 have been suggested to confer differential carcinogenicity. To investigate risk implications of HPV16 variants among Chinese women, a case-control study was conducted with 298 cervical cancer patients and 85 controls (all HPV16-positive). HPV16 isolates were predominantly of the A variant lineage, and variants of A4 (previously named “Asian”) sublineage were common. A4/Asian variants were significantly associated with increased risk of cervical cancer compared to A1-3 (OR = 1.72, 95% CI = 1.04-2.85). Furthermore, a meta-analysis including 703 cases and 323 controls from East Asia confirmed the association (OR = 2.82, 95% CI = 1.44-5.52). In conclusion, A4 variants appear to predict higher risk of cervical cancer among HPV16-positive women, which may provide clues to the genetic basis of differences in the carcinogenicity of HPV16 variants.

Citation Format: Dong Hang, Yin Yin, Jing Han, Jie Jiang, Hongxia Ma, Shuanghua Xie, Xiaoshuang Feng, Kai Zhang, Zhibin Hu, Shen Hongbing, Gary M. Clifford, Min Dai, Ni Li. Analysis of human papillomavirus 16 variants and risk for cervical cancer in Chinese population. [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 3444.
Abstract 3449: Placental characteristics and risk of cryptorchidism among populations at high and low risk of testicular germ cell tumors
Authors: Ghazarian Armen A. , Trabert Britton , Graubard Barry , Longnecker Matthew , Klebanoff Mark , McGlynn Katherine
Published: July 2016

Background: Testicular germ cell tumors, which are significantly more common among white men than black men in the U.S., are thought to be part of a Testicular Dysgenesis Syndrome (TDS) that also includes impaired fertility, hypospadias and cryptorchidism. The etiology of the TDS conditions is not well understood, but the in-utero milieu is likely to be a significant factor. As the placenta is a critically important determinant of the in-utero milieu, placental characteristics may play a role in determining risk of the TDS conditions. Prior evidence suggests that placental weight, in particular, may be associated with cryptorchidism.

Methods: We examined placental characteristics (weight, thickness, placental weight/birth weight ratio, infarct size, disorders of membrane development, presence of macrophages in the amniotic fluid) and cryptorchidism in a nested case-control study within the Collaborative Perinatal Project (CPP). The CPP was a maternal-child cohort study conducted in 12 medical centers in the U.S. between 1959 and 1965. Diagnoses of cryptorchidism made during the first year of life were included in the case group. The analysis contrasted 413 (232 white, 181 black) boys with cryptorchidism to 23,799 (12,092 white, 11,707 black) boys without cryptorchidism. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression, stratified by race.

Results: Among white boys, cryptorchidism was significantly associated with circummarginate placenta (OR: 1.7, 95% CI: 1.1-2.7) or a combination of circummarginate/circumvallate (OR: 1.3, 95% CI: 1.0-1.8) placenta. Among black boys, cryptorchidism was significantly associated with having at least one placental infarct greater than 3 cm (OR: 2.3, 95% CI: 1.1-4.8) and with placental weight in the lower (OR: 1.7, 95% CI: 1.1-2.6) or higher (OR: 1.5, 95% CI: 1.0-2.3) tertile compared with the middle tertile. No significant associations were found between cryptorchidism and the other placental characteristics in either white or black boys.

Conclusion: These results suggest that there may be associations between cryptorchidism and certain placental characteristics which differ between white and black births. The race-specific findings suggest an area where future research may prove fruitful.

Citation Format: Armen A. Ghazarian, Britton Trabert, Barry Graubard, Matthew Longnecker, Mark Klebanoff, Katherine McGlynn. Placental characteristics and risk of cryptorchidism among populations at high and low risk of testicular germ cell tumors. [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 3449.
Abstract 345: Olive oil-based oleocanthal and bioisosteres as c-Met inhibitors for the control of triple negative breast cancer
Authors: Ebrahim Hassan Y. , Mohyeldin Mohamed M. , Siddique Abu Bakar , Akl Mohamed R. , Ibrahim Mostafa , El Sayed Khalid A.
Published: July 2016

Breast cancer is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. Dysregulation of c Met correlates with aggressive proliferation, invasive character, and pathological motility, especially in triple negative breast cancer (TNBC). The Mediterranean diet is known to reduce the incidence of breast and colon malignancies. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the RTK c-Met. Oleocanthal selectively inhibited the proliferation, migration and invasion of several c-Met dependent breast and prostate tumor cell lines. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Several oleocanthal bioisosteres have been semisynthized of which the analog HVS have shown significant activity improvement against breast cancer in vitro and in vivo models. Selectivity profiling against a TKs panel, structurally related to c-Met, suggested the HVS has high selectivity to both Met and ABL1 kinases. Overexpression of ABL1 kinase is implicated in the progression of several solid tumors concomitantly with c-Met activation, including breast, colon, lung and other cancers. ABL1 interconnects oncogenic Met and p53 pathways and hence dual blockage of c-Met and ABL1 activation adds significant advantages over currently approved c-Met inhibitors and may justify its potent in vitro and in vivo activities. Therefore, the dual c-Met/ABL1 inhibitor HVS could not only be effective in slowing TNBC progression but also could prevent drug resistance. Detailed molecular and cellular mechanistic studies of oleocanthal and its bioisosteres indicate their potential for future use to control TNBC and other c-Met-dependent malignancies. This study was supported by NIH/NCI project 1R15CA167475-01.

Citation Format: Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Abu Bakar Siddique, Mohamed R. Akl, Mostafa Ibrahim, Khalid A. El Sayed. Olive oil-based oleocanthal and bioisosteres as c-Met inhibitors for the control of triple negative breast cancer. [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 345.
Abstract 3450: Epidemiological factors associated with breast cancer in young women
Authors: Toro Allyson L. , Hueman Matthew T. , Shriver Craig D. , Ellsworth Rachel E.
Published: July 2016

Background: Although breast cancer in young women (YW, <40 years) only accounts for ∼7% of cases diagnosed annually, tumors in young patients have more aggressive characteristics and higher mortality rates. The cost of breast cancer increases significantly with more aggressive tumors in terms of treatment costs, physical and psychosocial effects on the patient and her family, and lost productivity. Improved understanding of factors associated with etiology of breast cancer in YW is critical to developing more effective prevention strategies and improved treatments, reducing the burden of breast cancer in this population.

Methods: The Clinical Breast Care Project database was queried to identify all YW with invasive breast cancer or benign breast conditions diagnosed after surgical evaluation between 2001 and 2014 that had questionnaire data available from the time of diagnosis. Epidemiological factors including reproductive and health history and lifestyle choices were using Student's t-tests and chi-square analysis with P<0.05 defining significance.

Results: Neither ethnicity nor family history differed significantly between YW with and without breast cancer. Reproductive factors that differed significantly between groups include longer use of oral contraceptives (P<0.001, 93 compared to 66 months), older age at first full-term pregnancy (FFTP, P = 0.002, 24.5 compared to 22.7 years), and longer duration of breastfeeding in parous YW (P = 0.024, 15.1 compared to 10.4 months) in YW with invasive breast cancer compared to those with benign conditions. YW with invasive breast cancer were also significantly more likely to be married (P = 0.043, 78% compared to 68%) and less likely to exercise (P = 0.003, 31% compared to 17%) compared to those with benign breasts.

Conclusions: Of the factors evaluated, including reproductive history, lifestyle choices, and co-morbidities, only five differed significantly between YW with and without invasive breast cancer. Paradoxically, breastfeeding, which has been associated with reduced the risk of breast cancer, was higher in YW who developed invasive breast cancer. In contrast, parity and use of oral contraceptives are associated with transient increases in breast cancer risk. The older age at FFTP of YW with invasive breast cancer combined with the significantly longer exposures to oral contraceptives may create an environment within the breast favorable to tumor initiation and progression.

Citation Format: Allyson L. Toro, Matthew T. Hueman, Craig D. Shriver, Rachel E. Ellsworth. Epidemiological factors associated with breast cancer in young women. [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 3450.