bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 812: Assessing combinations of FDA approved chemotherapy in childhood sarcoma cell lines
Authors: Yu Diana , Cubitt Christopher , Sullivan Daniel , Reed Damon 
Published: May 2015

Abstract
Background: Sarcomas are a heterogeneous group of mesenchymal malignant tumors that make up approximately 15% of all childhood tumors and represent the fourth most common group of malignancies in children, remaining common in young adults with cancer as well. While over 35 agents have been FDA approved for adult carcinomas in the past 3 years, little progress has been made in incorporating new agents into the chemotherapy plans for pediatric sarcomas in the past few decades. A system to rapidly evaluate many agents and combinations of agents which can immediately be translated into clinical trials in a clinically relevant manner is needed.
Methods: Here, we seek to examine the therapeutic activity of single agent and combinations of FDA approved chemotherapy agents using high-throughput screening platforms, based on well-established childhood cancer cell line models for most prevalent forms of pediatric bone sarcomas (osteosarcoma and Ewing sarcoma). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds at clinically-relevant concentrations and time of exposures that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results to the clinical setting. Fifty-four agents, mainly FDA approved but also including agents with promising mechanism of action or preclinical data were screened across 5 cell lines for each histology. Caspace glo and cell titer glo assays were used to determine apoptosis and cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in 2 drug combinations to evaluate for synergy with careful attention to metabolism pathways, existing clinical data for combinations, and non-overlapping toxicities. Combinations of FDA approved agents with promising therapeutic efficacy and predicated non-overlapping toxicities will be translated to the clinic using the established Sunshine Project network.
Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability and induced up regulation of caspase3/7 activities across all cell lines. These findings suggest promising opportunities for developing combinational approach to treating childhood bone sarcomas and can be utilized to explore other pediatric tumors with existing cell lines.
Citation Format: Diana Yu, Christopher Cubitt, Daniel Sullivan, Damon Reed. Assessing combinations of FDA approved chemotherapy in childhood sarcoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 812. doi:10.1158/1538-7445.AM2014-812
Abstract 813: A combination of cisplatin, irinotecan, and paclitaxel (CIP) as frontline treatment of patients with metastatic esophageal cancer (mEC)
Authors: Giever Thomas A. , Ritch Paul S. , Thomas James P. , Wiebe Lauren A. , Haasler George B. , Gasparri Mario G. , Johnstone David , Johnstone Candice A. , Gore Elizabeth M. , George Ben 
Published: May 2015

Abstract
Introduction: Median survival associated with mEC is 9-12 months. While systemic therapy is the mainstay of treatment for mEC, there is no consensus regarding the best frontline chemotherapy combination. We evaluated the efficacy of CIP (Cisplatin 30 mg/m2, Irinotecan 50 mg/m2 and Paclitaxel 50 mg/m2 on days 1 and 8 of a 21 day cycle) in patients with mEC.
Methods: We performed a retrospective review to identify mEC patients at the Medical College of Wisconsin (MCW) who were treated with frontline CIP between January 1, 2005 and December 31, 2010. Relevant clinical information was collected through a review of the electronic medical record. This study was approved by the Institutional Review Board at MCW.
Results: We identified 13 patients who were treated with CIP as frontline therapy for mEC. The median age at diagnosis was 59 years (range 48-71 years), 12 (92%) patients were male, and 9 patients (69%) had adenocarcinoma with the remaining being squamous cell carcinoma. Eleven patients (85%) presented with metastatic disease, while 2 patients (15%) were diagnosed with metastatic disease after having undergone initial surgical resection with disease free intervals of 39 and 14 months respectively. The most common sites of metastases were lymph nodes (11 patients), liver (6 patients), lung (4 patients), bone (3 patients), and peritoneum (2 patients); 77% of patients had at least 2 sites of metastases. The median number of chemotherapy cycles administered was 7 (range 1-14). Four patients (31%) developed grade 3/4 toxicities including neutropenia in 3 patients, nausea in 1 patient, and anemia in 1 patient. One patient (8%) had a complete response (CR), 7 patients (54%) had a partial response (PR), 2 patients (15%) had stable disease (SD), and 3 patients (23%) developed progressive disease (PD). The median progression free survival (PFS) was 5 months (range 0-29 months) and the median overall survival (OS) was 10 months (range 3-36 months).
Conclusion: CIP is an active and well tolerated regimen in patients with mEC that merits prospective evaluation.
Citation Format: Thomas A. Giever, Paul S. Ritch, James P. Thomas, Lauren A. Wiebe, George B. Haasler, Mario G. Gasparri, David Johnstone, Candice A. Johnstone, Elizabeth M. Gore, Ben George. A combination of cisplatin, irinotecan, and paclitaxel (CIP) as frontline treatment of patients with metastatic esophageal cancer (mEC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 813. doi:10.1158/1538-7445.AM2014-813
Abstract 829: The novel camptothecin derivative and IAP inhibitor FL118 is an effective treatment for irinotecan-refractory colorectal cancer
Authors: Westover David , Ling Xiang , Liu Xiaojun , Lam Hong , Gongora Celine , Rio Maguy Del , Li Fengzhi 
Published: May 2015

Abstract
The current standard care for metastatic colorectal cancer is combination of leucovorin, 5-fluorouracil, and irinotecan. Irinotecan is a semisynthetic analogue of the alkaloid camptothecin and functions by inducing DNA double-strand breaks through inhibition of topoisomerase I (Top1) activity. The camptothecin-derived Top1 inhibitors irinotecan and topotecan are effective anti-cancer agents that are currently utilized as first-line therapies in several human cancers. Unfortunately, resistance to these agents usually develops during treatment, often through upregulation of the drug efflux pump ABCG2, an ATP-binding cassette transporter. By increasing the rate of drug export, ABCG2 decreases the amount of irinotecan or topotecan that accumulates intracellularly, thereby protecting cancer cells from the cytotoxic effects of these drugs. Therefore, a camptothecin derivative that is also a poor substrate for ABCG2 could potentially overcome ABCG2-induced irinotecan resistance and restore therapeutic efficacy. Our lab recently reported on a novel camptothecin derivative, FL118, which shows strong anti-cancer activity both in vitro and in vivo. Here we report the ability of FL118 to overcome irinotecan resistance. Several irinotecan-resistant colon cancer cell lines derived from HCT116 were treated with either FL118 or SN38, the active metabolite of irinotecan. We observed a decrease in the potency of SN38 in irinotecan-resistant cells that overexpressed ABCG2 compared to cells that did not overexpress ABCG2. In contrast, this loss of potency was not observed for FL118. To confirm that the decrease in potency was ABCG2-dependent, HCT116-A2, an ABCG2 overexpressing cell line, was treated with SN38 or FL118 in the presence or absence of Ko143, an ABCG2 inhibitor. We observed that Ko143 could restore potency to SN38 in HCT116-A2 cells, confirming that irinotecan resistance in HCT116-A2 cells is mediated by ABCG2. However, Ko143 could not modulate the potency of FL118, further suggesting that FL118 is not affected by ABCG2 activity. Similar results were observed in studies with anti-ABCG2 shRNA. Based on these observations, we conclude that FL118 is not a substrate for ABCG2, and that further testing is warranted to determine whether FL118 would be an effective anti-cancer agent for patients with irinotecan-resistant colorectal cancer overexpressing ABCG2.
Citation Format: David Westover, Xiang Ling, Xiaojun Liu, Hong Lam, Celine Gongora, Maguy Del Rio, Fengzhi Li. The novel camptothecin derivative and IAP inhibitor FL118 is an effective treatment for irinotecan-refractory colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 829. doi:10.1158/1538-7445.AM2014-829
Abstract 84: Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer
Authors: Uemura Hirotsugu , Kura Yurie , Ando Naomi , Fukushima Emiko , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Velasco Marco A. De 
Published: May 2015

Abstract
The prostate-specific PTEN conditional knockout (K/O) mouse model has been extremely useful as tool to investigate the biology of the tumorigenesis process, particularly during early tumor development. However, cancer progression is gradual with a low metastatic rate. This feature poses a challenge to this model when used for survival studies and end-stage biological characterization of prostate cancer. Inactivation of P53 is a characteristic that is frequent in advanced prostate cancer. To address this issue, we generated series of double K/O mice based on either P53 loss or gain of function in combination with PTEN inactivation. Conditional inactivation of both PTEN and P53 results in the development of aggressive tumors compared to PTEN K/O mice. Homozygous PTEN/P53-mutants mice grow prostate tumors at a faster rate and experience dramatically reduced survival. Homozygous double K/O mice also developed a higher frequency and number of metastases. Furthermore, haploinsufficient P53 gain of function mutations contributed to an invasive cancer phenotype compared to P53 loss of function haploinsufficient tumors. In conclusion, our analyses demonstrate that synchronous inactivation of PTEN and P53 promotes an aggressive prostate cancer and provides rationale that supports that use of such models is better suited for studies requiring long-term survival and end-stage cancer characterization.
Citation Format: Hirotsugu Uemura, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco. Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 84. doi:10.1158/1538-7445.AM2014-84
Abstract 861: Survivin-mediated adaptive response: a risk factor for IGRT
Authors: Grdina David J. , Murley Jeffrey S. , Miller Richard C. , Woloschak Gayle E. , Li Jian Jian , Weichselbaum Ralph R. 
Published: May 2015

Abstract
Exposure of cells to very low doses of ionizing radiation can induce an enhanced resistance or adaptive response to a subsequent larger radiation dose as demonstrated by an increase in cell survival. Expression of a radio-adaptive response has been attributed to pro-survival signaling processes induced by very low radiation doses in the range of 5 to 100 mGy. The radiation-induced adaptive response is gaining considerable attention due in part to the expanding use of imaging technologies such as computerized axial tomography and portal imaging to monitor tumor response and positioning during multi-dose standard radiation therapy protocols. The focus of this study was to investigate whether this process could occur when the very small imaging radiation dose was administered prior to or following the administration of the first of two typically used radiation therapy level doses. SA-NH mouse sarcoma cells and SA-NH cells stably transfected with mutated IκBα (SA-NH+mIκBα1) to inhibit the activation of NFκB were grown to confluence in vitro or as tumors in the right hind leg of C3H mice. Percentage of cell survival, apoptosis frequencies and survivin protein levels were determined as a function of radiation conditions and transfection of cells with survivin siRNA. A significant radio-adaptive response was observed in cells exposed to 5 mGy - 100 mGy 15 min to 6 h prior to or after irradiation with the first of two 2 Gy therapeutic radiation doses and was associated with a concomitant reduction in apoptosis frequencies and a rapid elevation in survivin protein levels. The very low dose radiation-induced elevation in survivin levels, the reduction in apoptosis frequencies and enhanced cell survival were not observed in SA-NH+mIκBα1 cells or SA-NH cells transfected with survivin siRNA. We have identified a very low radiation dose-induced survivin-mediated adaptive response that could compromise therapeutic outcomes associated with the increased usage of imaging procedures in radiation therapy. This work was supported by NIH/NCI grant R01 CA132998 and DOE Low Dose Program/Project Grant DE-SC0001271 (D.J.G.)
Citation Format: David J. Grdina, Jeffrey S. Murley, Richard C. Miller, Gayle E. Woloschak, Jian Jian Li, Ralph R. Weichselbaum. Survivin-mediated adaptive response: a risk factor for IGRT. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 861. doi:10.1158/1538-7445.AM2014-861
Abstract 864: Increased rates of radiation pneumonitis in patients receiving stereotactic ablative radiotherapy for central versus peripheral lung tumors
Authors: Chaudhuri Aadel A. , Tang Chad , Trakul Nicholas , Wynne Jacob , Loo Billy , Diehn Maximilian 
Published: May 2015

Abstract
Purpose: Treatment of central lung tumors with stereotactic ablative radiotherapy (SABR) has been associated with higher rates of toxicities than patients with peripheral tumors. Here we report our institution's experience in treating central lung tumor patients with SABR, compared to patients treated for peripheral lung tumors.
Methods: We retrospectively reviewed outcomes in 82 patients with a total of 96 primary or metastatic lung tumors treated by SABR. The cohort included 47 central and 49 peripheral tumors and all were treated with 50 Gy in 4-5 fractions. Outcomes and radiation-associated toxicities were compared between the two groups, not including patients in whom central and peripheral tumors were concurrently treated (8 such patients). Dosimetric analysis was performed on patients with central tumors to determine max point dose (MPD) and volumetric max dose (Vmax) to central structures.
Results: Median follow-up time was 15 months (range 1 to 59 months). Median overall survival was 34 and 40 months (p=0.75) for patients with central and peripheral tumors, respectively. We observed no hemoptysis and no grade 5 toxicities. Rates of symptomatic toxicity were higher in patients with central tumors (grade 2+, 38% vs. 11%, p=0.0056) but were equivalent for severe toxicity (grade 3+, 5.4% vs. 5.4%, p=0.93). The vast majority of toxicities were due to radiation pneumonitis, incidence of which was significantly greater in patients with central tumors (grade 2+, 30% vs. 2.7%, p=0.0021; grade 3+, 5.4% vs. 0%, p=0.15). Dosimetric analysis of 36 central tumor treatment plans revealed that 23 (64%) exceeded at least one of the dose constraints used in RTOG 0813, most commonly for central airway. Rates of grade 2+ pneumonitis were not significantly different between patients exceeding RTOG 0813 central airway dosing constraints vs. those meeting them (24% vs. 20%, p=0.69), but trended towards significance for grade 3+ radiation pneumonitis, with patients exceeding RTOG 0813 central airway dosing constraints experiencing higher rates (0% vs. 13%, p=0.095).
Conclusions: Central lung tumor patients treated with SABR appear to have greater risk for symptomatic radiation pneumonitis than patients with peripheral tumors. Exceeding RTOG 0813 dosimetric constraints for central airway may predispose to higher risk for severe radiation pneumonitis.
Citation Format: Aadel A. Chaudhuri, Chad Tang, Nicholas Trakul, Jacob Wynne, Billy Loo, Maximilian Diehn. Increased rates of radiation pneumonitis in patients receiving stereotactic ablative radiotherapy for central versus peripheral lung tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 864. doi:10.1158/1538-7445.AM2014-864
Abstract 869: Evaluate breast cancer diagnostic antibody specificity by using high density protein microarray technology
Authors: Ma Donghui , Chen Jian , Fu Wei , McDowell Julie , Yuan Kehu 
Published: May 2015

Abstract
Detection sensitivity and target specificity are the two key features for a good diagnostic monoclonal antibody. There are a number of well-established technology platforms to quantitatively measure antibody affinity. However, there is no complete technology solution to evaluate antibody target specificity. Antibody cross-reactivity could lead to false diagnostic reports. Currently, high density protein microarray technology is the best technology platform available for antibody specificity evaluation. Here we will showcase how we utilized protein microarray technology to evaluate target specificity for a couple of commonly used breast cancer IHC diagnostic antibodies. Our data suggested that cross-reactivity is one of the reasons to create off-target staining for breast cancer diagnostics. We will also show how we can utilize OriGene protein microarray chip technology to develop UltraMABs, the Ultra-specific monoclonal antibodies for anatomic pathology application.
Citation Format: Donghui Ma, Jian Chen, Wei Fu, Julie McDowell, Kehu Yuan. Evaluate breast cancer diagnostic antibody specificity by using high density protein microarray technology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 869. doi:10.1158/1538-7445.AM2014-869
Abstract 891: Urinary ADAM12 levels detect the presence of pancreatic cancer
Authors: Roy Roopali , Zurakowski David , Kulke Matthew , Moses Marsha A. 
Published: May 2015

Abstract
Pancreatic malignancies are the fourth leading cause of all cancer-related deaths of both men and women in the United States. Each year, approximately 32,000 new patients are diagnosed with this disease and nearly the same number die from it. A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET) present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. The combination of poor prognosis and late presentation of pancreatic cancer patients highlights the urgent need for the development of effective, early detection strategies for this disease. Our laboratory has established a comprehensive biomarker discovery initiative whose objective is to identify proteins present in urine of cancer patients, to determine whether their presence might be relevant to disease status and stage and to validate their diagnostic and prognostic efficacy in large scale clinical trials. In the current study, our goal was to determine whether ADAM12 (a disintegrin and metalloprotease 12) could be detected in the urine of patients with pancreatic malignancies and whether ADAM12 levels might serve as an independent predictor of disease status. Retrospective analyses of urine samples (n=130) from PDAC and pNET patients as well as age- and sex-matched controls were conducted. Urinary ADAM12 levels were determined using a monospecific ELISA system. In addition, ADAM12 protein expression in tumor and normal pancreatic tissues was analyzed via immunohistochemistry (IHC). Multivariable logistic regression analyses indicated that, when controlling for age and sex, urinary ADAM12 could serve as significant independent predictor for distinguishing PDAC (P&lt;0.001) and pNET (P&lt;0.008) patients from healthy controls. Kaplan-Meier analysis of estimated patient survival stratified by urinary ADAM12 levels indicated a significantly shorter patient survival time for PDAC patients with high ADAM12 levels (P=0.015) compared to patients with lower urinary ADAM12. In addition, IHC analysis indicated that ADAM12 protein expression was upregulated ∼4-fold in Grade I-III PDAC compared to normal pancreatic tissue. Taken together, our results suggest that the measurement of ADAM12 levels may have diagnostic value in detection and/or clinical monitoring of disease status in patients with pancreatic malignancies. [Supported by: The Advanced Medical Foundation]
Citation Format: Roopali Roy, David Zurakowski, Matthew Kulke, Marsha A. Moses. Urinary ADAM12 levels detect the presence of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2014-891