bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4706: Wide surgical margins are of prognostic importance in GIST.
Authors: Ahlen Jan , Branstrom Robert , Nilsson Inga-Lena 
Published: August 2014

Abstract
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract and even in the era with molecularly targeted agents is surgery the mainstay of treatment and the only treatment that could lead to cure. Microscopically negative margins are today accepted as sufficient margins for cure while tumor rupture is known to result in poor prognosis and therefore taken into account in prognostic models. In other types of soft tissue sarcoma has wide margins been known to be of importance for recurrence while this has not been shown in GIST.
Methods: 116 patient were included in the study, 55 male and 61 female, mean age 61 years (10-86) and mean follow-up 73 month (4,6-365) that has been evaluated for surgical margins at the time for surgery or at referral to our institution. The criteria used has been those used for sarcoma in other locations were “Wide margins” are defined as 3 cm marginal in the organ of origin combined with an completely intact peritoneal surface covering the tumor. In cases where the tumor is stucked to surrounding tissue or organ, that part has been resected “un bloc” with the tumor. “Marginal margins” are defined as R0 resection with less then 3 cm and “Intralesional margin” is when the tumor is shelled out or damage to surrounding peritoneal surface or judged as R1 resection. Local recurrence has been defined as recurrence at site of origin or intraabdominal recurrence of tumor in the peritoneum and metastatic disease when recurrence is distant metastasis.
Results: We found 48 cases with wide margins(3 recurrence), 39 with marginal margins (15 recurrence) and 29 with intralesional margins (17 recurrence). There was significant difference calculated as Kaplan-Meier for both local recurrence (p=0,00016), distant metastasis (p= 0,004) and survival (p= 0,0047) and in cox regression analysis hazard ratio were 7,4 for marginal margins and 8,08 for intralesional margins compared to wide margins and this was not correlated with size or site (p= 0,007).
Conclusion: Surgical margins is of great importance in GIST both for local recurrence, distant metastasis and survival and patient with GIST should be operated with wide margins, in accordance with principals of other sarcoma.
Citation Format: Jan Ahlen, Robert Branstrom, Inga-Lena Nilsson. Wide surgical margins are of prognostic importance in GIST. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4706. doi:10.1158/1538-7445.AM2013-4706
Abstract 4716: Chronic alcohol consumption activates the LiTAF pathway in melanoma-bearing mice.
Authors: Marron Andrew , Zhang Hui , Zhu Zhaohui , Meadows Gary G. 
Published: August 2014

Abstract
We previously reported that chronic alcohol consumption increases myeloid-derived suppressor cells (MDSC) and compromises melanoma-specific CD8+ T cells in B16BL6 melanoma-bearing mice; however, the underlying mechanism has not been elucidated. Activation of LPS-induced TNF-α factor (LiTAF) gene leads to up-regulation in the expression of various cytokines, chemokines and growth factors such as TNF-α, IL-1β, and VEGF, which are inducers of MDSC. Alcohol consumption is associated with the leakage of LPS into the blood. However, it is not known whether alcohol consumption modulates the expression of LiTAF. Herein, we examined the effects of alcohol and subcutaneous inoculation of melanoma in mice on the expression of LiTAF and its downstream cytokines, chemokines and growth factors. Female C57BL/6 mice were given 20% (w/v) alcohol for three to six months followed by subcutaneous inoculation of 2x105 B16BL6 melanoma cells. Two weeks after tumor inoculation, the expression of LiTAF and related cytokine genes in the spleen were examined by RT-PCR. Chronic alcohol consumption dramatically up regulated the expression of LiTAF in the spleen of melanoma-bearing mice; however, expression was almost undetectable in the spleen of corresponding water-drinking mice. The expression of IL-1β, IL-10, TNF-α, CCL5, and VEGF-β was also significantly up regulated by alcohol. These results indicate that chronic alcohol consumption activates the LiTAF pathway and up regulates the expression of the downstream cytokines, chemokines and growth factors. The up regulation of these cytokines could contribute to the induction of MDSC and inhibition on CD8+ T cells.
(Supported by funds received from the Summer Undergraduate Research Fellowship (SURF) Program, from NIH grants R01 AA07193 and K05AA017149, and from funds provided for medical and biological research by the State of Washington Initiative Measure No. 171).
Citation Format: Andrew Marron, Hui Zhang, Zhaohui Zhu, Gary G. Meadows. Chronic alcohol consumption activates the LiTAF pathway in melanoma-bearing mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4716. doi:10.1158/1538-7445.AM2013-4716
Abstract 4717: Lymphotoxins activate NF-κB-mediated inflammatory and survival pathways in head and neck squamous cell carcinomas.
Authors: Cheng Tsu-Fan , Yang Xinping , Coupar Jamie , Si Han , Lee Steven , Zhang Jialing , van Waes Carter , Chen Zhong 
Published: August 2014

Abstract
Head and neck squamous cell carcinomas (HNSCC) are highly inflammatory and preferentially metastasize to lymph nodes (LN). HNSCC exhibit constitutively activated canonical and alternative NF-κB pathways, but the upstream signals activating these NF-κB pathways have not been well characterized. We hypothesized that immune regulatory cytokines Lymphotoxin (LT) α and β produced by tumor and/or LN cells could be critical in upstream signal activation of NF-κB in HNSCC. Although LTs and their receptors (LTβR and TNFR) are known to be expressed and produced by lymphocytes, we found that LTα and β, and their receptors LTβR and TNFR, are also expressed and produced in a subset of HNSCC cell lines and tumor tissue specimens, when compared with primary human oral mucosal cells. LTα activated both canonical and alternative NF-κB pathways, as indicated by induction of nuclear translocation of NF-κB subunits, RELA, cREL, RELB, p52 in a time dependent manner. In contrast, LTβ mainly activated the alternative NF-κB pathway, enhancing nuclear translocation of RELB and p52. In addition, LTβ-mediated gene expression was examined by Illumina bead microarray platform, and the top pathways of upregulated genes included NF-κB, immunoregulatory, inflammatory, and survival signaling pathways. Our data suggested that HNSCC expressed lymphotoxins and their receptors could be critical factors that contribute to the constitutively activated NF-κB, inflammatory and survival signaling previously implicated in HNSCC pathogenesis. Understanding of lymphotoxin-mediated cross-talk with these inflammatory and survival signaling pathways, could provide a missing link between the inflammation and tumorigenesis in the tumor microenvironment.
Citation Format: Tsu-Fan Cheng, Xinping Yang, Jamie Coupar, Han Si, Steven Lee, Jialing Zhang, Carter van Waes, Zhong Chen. Lymphotoxins activate NF-κB-mediated inflammatory and survival pathways in head and neck squamous cell carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4717. doi:10.1158/1538-7445.AM2013-4717
Abstract 4740: Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model.
Authors: Alizadeh Darya , Trad Malika , Katsanis Emmanuel , Larmonier Nicolas 
Published: August 2014

Abstract
Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of cells equipped with the ability to inhibit T lymphocyte-mediated immune responses. A significant increase in the number of MDSC has been reported in the blood, secondary lymphoid organs and tumor beds in tumor-bearing animals and in patients with many types of cancers. MDSC frequency correlates with the disease stage and prognosis. These cells impair CD8+ cytotoxic T lymphocyte (CTL)-mediated anti-tumor immunity by different overlapping mechanisms such as reactive oxygen species or immunosuppressive cytokine production. Importantly, MDSC elimination or inactivation substantially enhances the efficiency of immunotherapy. Multiple studies have lent support to the concept that some anti-neoplastic molecules, besides their conventional direct cytotoxic influence on cancer cells, may also exhibit immunostimulatory effects, thereby promoting anti-tumor immunity. We present results demonstrating that doxorubicin, utilized in multiple chemotherapeutic regimens and known to trigger an immunogenic type of cancer cell death, dramatically reduces the number of tumor-induced MDSC in the murine mammary tumor model 4T1. Elimination of these suppressive cells occurs by an apoptotic process. In addition, residual MDSC isolated from doxorubicin-treated animals are significantly impaired in their immunosuppressive function. Of particular interest, the number of apoptotic CD4+ or CD8+ T lymphocytes is not augmented in mice administered with doxorubicin compared to untreated animals. We further demonstrate that doxorubicin-mediated elimination of MDSC is associated with enhanced T and NK cell activation, proliferation and expression of Perforin and Granzyme B. Lastly, we evaluated a chemoimmunotherapeutic strategy associating doxorubicin with T helper-1 or T helper-17 lymphocytes generated and activated in vitro. Our results indicate that this combination regimen hinders tumor development as evidenced by reduced number of 4T1 metastatic nodules in the lungs of treated animals. This therapeutic effect is associated with an increased cytotoxic activity of CD8+ T lymphocytes in the spleen of the treated mice. These observations thus highlight a new application of doxorubicin as a MDSC depleting agent and further advocate for the implementation of this drug in cancer immunotherapy approaches.
Citation Format: Darya Alizadeh, Malika Trad, Emmanuel Katsanis, Nicolas Larmonier. Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4740. doi:10.1158/1538-7445.AM2013-4740
Abstract 4741: Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor.
Authors: Wang Yangyang , Sabbatino Francesco , Ferrone Soldano , Wang Xinhui 
Published: August 2014

Abstract
In the US, about 10-20% of breast cancers are found to be triple-negative breast cancer(TNBC). Because of the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and human epidermal growth factor receptor 2 (HER2) amplification, TNBC does not benefit from the currently available targeted therapies. Furthermore, recent molecular analysis of TNBC cell lines and lesions has suggested that these tumors might be enriched with cancer initiating cells (CICs). This possibility is consistent with the failure of conventional therapies to control disease progression, because according to the cancer stem cell theory, CICs play a major role in disease recurrence and metastatic spread, the two major causes of patient mortality. These findings and the lack of curative therapy for any TNBC patient with metastatic disease emphasize the need to develop effective novel therapies for this type of breast cancer. To address this need, we have developed a combinatorial immunotherapy, which eliminates both differentiated TNBC cells and TNBC CICs. The tumor antigen we have selected as a target is chondroitin sulfate proteoglycan (CSPG)4, since this membrane bound tumor antigen is expressed at high levels on both differentiated TNBC cells and TNBC CICs. CSPG4 plays a crucial role in the biology of TNBC cells, since it is involved in ERK and FAK signaling pathways which are associated with TNBC cell proliferation and migration. Furthermore, it is upregulated on activated pericytes in the tumor microenvironment. CSPG4-specific mAb 225.28 inhibits TNBC cell growth and migration. Moreover, it inhibits signaling pathways associated with TNBC cell growth and survival. It also can selectively inhibit neoangiogenesis in the tumor microenvironment, contributing to the elimination of TNBC cells, even those that do not express CSPG4. To enhance the targeting of TNBC CICs, immunotherapy is combined with the administration of an inhibitor (cyclopamine/ LDE225) of the Sonic Hedgehog Homolog (SHH) pathway which is activated in TNBC cells and, especially in TNBC CICs. Inhibition of TNBC CIC growth by mAb 225.28 is around 10%, but is enhanced up to about 70% when mAb 225.28 is combined with a SHH pathway inhibitor. Our in vitro findings strongly suggest that targeting CSPG4 with mAb 225.28 in combination with a SHH inhibitor may represent an effective strategy to eliminate differentiated TNBC cells and TNBC CICs.
Citation Format: Yangyang Wang, Francesco Sabbatino, Soldano Ferrone, Xinhui Wang. Inhibition of TNBC cell growth by CSPG4-specific mAb 225.28 with a Sonic Hedgehog pathway inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4741. doi:10.1158/1538-7445.AM2013-4741
Abstract 4749: Cyclophosphamide induces dose dependent apoptosis of CD4+FoxP3+ regulatory T cells relative to CD4+FoxP3- effector T cells in breast cancer patients.
Authors: Chen Gang , Leatherman James M. , Sunay Melek Erdinc , Emens Leisha A. 
Published: August 2014

Abstract
CD4+FoxP3+ regulatory T cells (Tregs) accumulate at tumor sites and within the peripheral blood of patients with a variety of cancers. Tregs suppress antigen-specific immune responses, and represent a major barrier to the efficacy of cancer immunotherapy. We previously conducted a dose-ranging study of low dose Cyclophosphamide (0, 200, 250, and 350 mg/m2) given one day prior to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting HER-2+ breast cancer vaccine in 28 patients with metastatic breast cancer. We found that vaccine-induced HER-2-specific immunity was best optimized by 200 mg/m2 CY, and that doses of CY higher than 200 mg/m2 suppressed antigen-specific immunity. To further explore the pharmacodynamic impact of CY on immune priming, we analyzed Tregs and effector CD4+ T cells present in peripheral blood mononuclear cells (PBMC) collected pre- and post-vaccination with or without CY by flow cytometry. We found that the percentage of CD4+FoxP3+ Tregs in PBMC did not change with vaccination alone. Conversely, CY at doses of either 200 or 250 mg/m2 selectively induced the apoptosis of CD4+FoxP3+ Tregs relative to CD4+FoxP3− effector T cells, and CY at 350 mg/m2 induced apoptosis of both CD4+FoxP3+ Tregs and CD4+FoxP3− effector T cells. Finally, CY at all doses selectively decreased CCR7−CD45RA− effector memory Tregs and increased CCR7+CD45RA+ naïve Tregs relative to vaccine alone. Collectively, these data suggest that low dose CY selectively induces apoptosis of CD4+FoxP3+ Tregs relative to CD4+FoxP3− effector T cells, providing a window for more efficient induction of vaccine-induced HER-2-specific immunity.
Citation Format: Gang Chen, James M. Leatherman, Melek Erdinc Sunay, Leisha A. Emens. Cyclophosphamide induces dose dependent apoptosis of CD4+FoxP3+ regulatory T cells relative to CD4+FoxP3- effector T cells in breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4749. doi:10.1158/1538-7445.AM2013-4749
Abstract 4753: Ablation of N1-S1 hepatocellular carcinoma in rat livers with nanosecond pulsed electric fields and induction of protective immunity.
Authors: Chen Ru , Sain Nova , Harlow Tye , Shires Peter , Long Gary , Heller Ricahrd , Beebe Stephen 
Published: August 2014

Abstract
Nanosecond pulsed electric fields (nsPEFs) could be used to ablate local tumor masses through minimally invasive or open surgery delivery, but further pre-clinical studies are needed. NsPEFs not only induces permanent permeabilization of cells, but also impacts intracellular organelles and result in apoptosis and other forms of cell death in vitro and in vivo. Hepatocellular carcinoma (HCC) is the third most common cancer cause of mortality worldwide. A diagnosis of HCC carries a guarded prognosis, especially when metastasis is documented. Presently, reliable, curative treatments without recurrence for very early, early, and intermediate HCC stages are still in urgent need of attention. In these studies, we specifically test the efficacy of nsPEFs in an orthotopic HCC rat tumor model. Orthotropic insertion of stably transfected (mcherry and/or luciferase) N1-S1 cells in Sprague Dawley rat livers was used as a model for treating HCC. Cells were treated with pulses with 100 ns duration and electric field strengths of 50 kV/cm. Different pulse numbers were applied. Recent results suggest that treatments of 300 or 500 pulses were more effective when separated by a 6 minute interval than when applied as a continuous, uninterrupted single treatment. However over time and treatment of more than 20 animals, 1000 nanosecond pulses treatment consistently showed successful ablation by effectively inducing tumor cell death. A single treatment of 1000 nsPEFs successfully induces cell apoptosis by activating caspase-9, caspase-3, but not caspase-8 in some cells, indicating induction of intrinsic apoptosis mechanisms as well as caspase-independent cell death, like that observed in vitro with human Jurkat cells. More importantly, rats successfully treated with 1000 pulses showed protective responses to a second N1-S1 intra-hepatic challenge injection of N1-S1 cells, suggesting a host immune response, which is under exploration. As an ideal potential therapy for HCC, nsPEFs treatment did not show any damaging impact on liver blood flow. These studies demonstrate for the first time, successful intra-hepatic treatment of HCC with a potential induction of immunogenic cell death and a host immune response after nsPEF ablation.
Citation Format: Ru Chen, Nova Sain, Tye Harlow, Peter Shires, Gary Long, Ricahrd Heller, Stephen Beebe. Ablation of N1-S1 hepatocellular carcinoma in rat livers with nanosecond pulsed electric fields and induction of protective immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4753. doi:10.1158/1538-7445.AM2013-4753
Abstract 4757: RARα1 as a novel drug target to improve conventional hormonal adjuvant therapy of breast cancer.
Authors: Chari Venkatesh V. , Trumbly Robert J. , d'A Salazar Marcela , Ratnam Manohar 
Published: August 2014

Abstract
Genetic or epigenetic changes must occur and be propagated for breast cancer cells to develop resistance to hormonal adjuvant therapies. This would require a basal level of cell cycling during hormone depletion or tamoxifen treatment. We have previously demonstrated that the retinoic acid receptor α1 (RARα1) apoprotein supports a basal level of proliferation in breast cancer cells that are either hormone depleted or treated with tamoxifen. This action of RARα1 was ligand-insensitive (reflecting a nonclassical mechanism) and involved the activation of growth supporting genes by the RARα1 apoprotein. As RARα1 is genetically redundant, we hypothesize that including targeted downregulation of RARα1 will improve the outcome of hormonal adjuvant therapy in breast cancer. Tissue array analysis indicated prevalence of RARα1 in clinical breast tumors covering a wide pathologic spectrum. We have synthesized a high affinity RARα-specific antagonist, AGN194301, as a means of selectively targeting RARα. AGN194301 did not affect the ability of RARα1 to support basal cell proliferation and did not alter the level of RARα1 protein. Preliminary SAR studies showed the positions at which the compound could be modified without abrogating its ability to bind to RARα. Further studies and strategies for attaining downregulation of RARα1 using modified versions of this compound will be discussed.
Citation Format: Venkatesh V. Chari, Robert J. Trumbly, Marcela d'A Salazar, Manohar Ratnam. RARα1 as a novel drug target to improve conventional hormonal adjuvant therapy of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4757. doi:10.1158/1538-7445.AM2013-4757