bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract MIP-076: A RECURRENT BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HIGH-GRADE SEROUS OVARIAN CARCINOMA
Authors: Kannan Kalpana , Coarfa Cristian , Chao Pei-Wen , Luo Liming , Wang Yan , Brinegar Amy E. , Hawkins Shannon M. , Milosavljevic Aleksandar , Matzuk Martin M. , Yen Laising 
Published: June 2017

Abstract
High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Using high-throughput RNAseq, we identify a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.
Citation Format: Kalpana Kannan, Cristian Coarfa, Pei-Wen Chao, Liming Luo, Yan Wang, Amy E. Brinegar, Shannon M. Hawkins, Aleksandar Milosavljevic, Martin M. Matzuk, and Laising Yen. A RECURRENT BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HIGH-GRADE SEROUS OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-076.
Abstract NTOC-093: SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS
Authors: Khalique Saira , Williamson Chris T. , Pemberton Helen , Wai Patty T. , Menon Malini , Brough Rachel , Leonidou Andri , Peck Barrie , Banerjee Susana , Natrajan Rachael C. , Lord Christopher J. 
Published: June 2017

Abstract
Epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy in the Western world. Ovarian clear cell carcinoma (OCCC), a distinct histological subtype, has a notably poor prognosis in the advanced setting compared to patients with high-grade serous ovarian cancer (HGSOC). Understanding why these patients have a poor outcome may be due to the underlying genetic drivers and their response to treatment. Dysregulation of the SWI/SNF complex is one of the most commonly occurring defects in solid cancers. Mutations in ARID1A (AT-rich interactive domain-containing protein 1A), a gene that encodes for BAF250A, forming part of the SWI/SNF chromatin remodeling complex, rarely occur in HGSOC but are common in ovarian clear cell carcinomas. The vast majority of these are loss of function frameshift or nonsense mutations, resulting in loss of protein function. In addition, loss of ARID1A expression in tumour specimens has been associated with a shorter progression free survival and chemoresistance in ovarian clear cell carcinoma (OCCC).
Despite the understanding that ARID1A defects are associated with tumourigenesis, targeted therapy approaches that exploit this deficiency have not as yet been developed. Our aims were to identify ways of targeting ARID1A deficient tumours by performing a large-scale functional genomics screen to identify actionable synthetic lethal effects. Using a high-throughput combination drug screen with a plate library of 80 compounds and a phase 1 compound, in isogenic ARID1A null and wild type HCT116 cells, we have identified candidate therapeutic approaches to targeting ARID1A mutant tumours that could be assessed in proof of concept clinical trials. We have undertaken subsequent high throughput drug screens in isogenic ARID1A null and wild type MCF10A cells that in we have identified a series of novel synthetic lethal effects. Assessment of this combinatorial approach in in vivo models of ARID1A mutant cancers is now underway. In conclusion, we have identified clinically actionable combinatorial approaches that may provide additional therapeutic benefit for ARID1A deficient patients.
Citation Format: Saira Khalique, Chris T. Williamson, Helen Pemberton, Patty T. Wai, Malini Menon, Rachel Brough, Andri Leonidou, Barrie Peck, Susana Banerjee, Rachael C. Natrajan and Christopher J. Lord,. SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-093.
Abstract NTOC-104: BEYOND RECIST1.1 : THE NEED FOR ALTERNATIVE DISEASE MEASUREMENT CRITERIA FOR CLINICAL TRIALS IN OVARIAN CANCER
Authors: Pepke Shirley , Rucker Trudy 
Published: June 2017

Abstract
BACKGROUND AND PURPOSE: The majority of ovarian cancer patients respond initially to platinum combination chemo therapy, however at least 70% will relapse and eventually die from recurrent platinum-resistant disease. Thus upon relapse, there is a high degree of interest in participation in clinical trials of novel treatments. However, the pattern of presentation of recurrent disease skews toward “non-measurable” by RECIST solid tumor response criteria, with a majority of patients presenting with diffuse, non-nodular disease and hence being excluded from participating in most trials. Yet these excluded patients may be the ones who would see most benefit from the tested drugs since drug efficacy would not be confounded with issues of penetration into bulky tumors. In addition, in cases where patients present with apparently isolated tumors that are amenable to measurement, the patient is currently forced to choose between surgical excision of the tumor, which retrospective studies suggest extends survival in appropriately selected cases, and keeping the tumor as measurable disease required for entry into a clinical trial. Finally, the current rapid development of targeted therapies, immunotherapies, and combinations means there are potentially many more trial opportunities than can be filled by the relatively small number of ovarian cancer patients, potentially slowing the translation from preclinical findings to actual patient treatment. Here we review the salient facts demonstrating the need for greater clinical trial access for patients with non-RECIST tumor presentation, issues of measuring tumor response, as well as some potential solutions.
METHODS: We used a literature search and an online patient survey to assess the impact that the RECIST requirements have on clinical trial participation by ovarian cancer patients. We also reviewed the literature for potential alternative approaches to tumor assessment that would be novel to either solid tumor trials as a whole or ovarian cancer specifically.
CONCLUSIONS: Expanding clinical trial access to ovarian cancer patients whose tumors do not meet RECIST requirements should accelerate progress in a way that benefits all stakeholders: patients, pharmaceutical companies, and researchers. Viable alternatives exist and more are under development. Ovarian cancer patients are eager to see these put into practice and are willing to help move this effort forward by participating in relevant validation trials. Adapting clinical trial structure and response criteria to accommodate non-measurable disease in ovarian cancer should be a high priority.
Citation Format: Shirley Pepke and Trudy Rucker. BEYOND RECIST1.1 : THE NEED FOR ALTERNATIVE DISEASE MEASUREMENT CRITERIA FOR CLINICAL TRIALS IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-104.
Abstract NTOC-106: FAK INHIBITION RE–SENSITIZES PLATINUM–RESISTANT SEROUS OVARIAN CANCER
Authors: Bean Lisa M. , Sulzmaier Florian J. , Anderson Kristen M. , Tancioni Isabelle , Butcher Cheyenne R. , Uryu Sean , Jean Christine , Lawson Christine , Chen Xiao Lei , Kleinschmidt Elizabeth G. , Kolev Vihren N. , Pachter Jonathan A. , Stupack Dwayne G. , Schlaepfer David D. 
Published: June 2017

Abstract
Most ovarian cancer patients respond well to surgical debulking and platinum-taxol chemotherapy. However, ~80% of patients with a complete response to therapy will exhibit tumor recurrence, and in time develop platinum and chemotherapy-resistant disease. It is hypothesized that recurrent disease emanates from the regrowth of microscopic clusters of chemotherapy-resistant tumor cells - also termed cancer stem cells (CSCs). Here, we find that cisplatin chemotherapy elevates focal adhesion (FAK) tyrosine kinase phosphorylation (Y397 FAK) in 3D ovarian tumor spheroids. Notably, FAK is not known as a DNA-damage sensing kinase. Instead, FAK is linked to integrin adhesion-, migration-, and CSC-promoting signaling pathways. In mouse tumors, CP-taxol chemotherapy increases FAK Y397 phosphorylation and aldehyde dehydrogenase (ALDH-1A1, a known markers of CSCs) in tumor areas not associated with necrosis. FAK Y397 phosphorylation is constitutively-elevated in CP-resistant ovarian cancer cells and nanomolar levels of FAK inhibitor (VS-4718) block 3D colony cell growth. Oral VS-4718 administration to mice reduces CP-resistant orthotopic tumor burden with a concomitant decrease in tumor-associated ALDH activity and secondary tumor-initiating capacity. CRISPR-mediated FAK knockout or VS-4718 treated ovarian carcinoma cells exhibit diminished ALDH-1A1 expression. Importantly, co-administration of VS-4718 enhances the anti-tumor effectiveness of CP-taxol chemotherapy in an orthotopic CP-resistant mouse tumor model. As CP activates FAK and FAK signaling sustains ovarian carcinoma CSC phenotypes, our results support the future testing of FAK inhibitors in combination with CP to prevent recurrent and chemo-resistant ovarian cancer.
Citation Format: Lisa M. Bean, Florian J. Sulzmaier, Kristen M. Anderson, Isabelle Tancioni, Cheyenne R. Butcher, Sean Uryu, Christine Jean, Christine Lawson, Xiao Lei Chen, Elizabeth G. Kleinschmidt, Vihren N. Kolev, Jonathan A. Pachter, Dwayne G. Stupack, and David D. Schlaepfer. FAK INHIBITION RE–SENSITIZES PLATINUM–RESISTANT SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-106.
Abstract TMEM-022: LYSOPHOSPHATIDIC ACID IN OVARIAN CANCER EPITHELIAL–TO–MESENCHYMAL TRANSITION
Authors: Dia Vermont P 
Published: June 2017

Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid found in elevated concentrations in ovarian cancer (OVCA) patients. The objective of this study was to define the mechanism of action by which LPA contributes to ovarian carcinogenesis focusing on epithelial-to-mesenchymal transition (EMT) and role of human macrophages. THP-1 human macrophages and A27801AP human OVCA cells were used and treated with LPA up to 40 µM for 24 h. In THP-1 human macrophages, LPA treatment led to a dose-dependent increase in IL-1β secretion from 333.5 pg/mL (untreated) to 581.9, 661.8 and 1270.1 pg/mL for 10, 20 and 40 µM LPA treatment. We then used the conditioned medium (CM) from THP-1 macrophages to determine the effect on A27801AP OVCA cells. LPA-treated THP-1 CM increased the expression of EMT transcription factors p65, Slug and Snail as compared to non-LPA-treated THP-1 CM and resting OVCA cells. When A27801AP OVCA cells were treated with LPA alone, 20 µM LPA led to the same significant increase in the expression of EMT transcription factors p65, Slug and Snail. In addition, LPA treatment reduced the expression of the epithelial marker E-cadherin while increasing the expression of mesenchymal markers N-cadherin and vimentin which might be associated with increased phosphorylation of extracellular regulated kinase 1/2. The data show the role of LPA in modifying not only OVCA cells but also macrophages that can be found in the tumor microenvironment to promote progression of OVCA by promoting EMT.
Citation Format: Vermont P Dia, Ph D. LYSOPHOSPHATIDIC ACID IN OVARIAN CANCER EPITHELIAL–TO–MESENCHYMAL TRANSITION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-022.
Abstract TMEM-025: IMPACT OF MESOTHELIN EXPRESSION ON THE METASTATIC SUCCESS OF OVARIAN CANCER
Authors: Hilliard Tyvette , Iwamoto Kyle , Loughran Elizabeth , Asem Marwa , Liu Yueying , Yang Jing , Tarwater Laura , Klymenko Yuliya , Johnson Jeff , Shi Zonggao , Stack M. Sharon 
Published: June 2017

Abstract
Ovarian cancer is the most lethal gynecological cancer in U.S. women. Poor 5-year survival rates (&lt;30%) are due to presentation of most women at diagnosis with advanced stage disease with widely disseminated intraperitoneal metastasis. However, when diagnosed before metastatic propagation the overall 5-year survival rate is &gt;90%. Metastasizing tumor cells grow rapidly and aggressively attach to the mesothelium of all organs within the peritoneal cavity, including the parietal peritoneum and the omentum, producing secondary lesions. Mesothelin (MSLN), a 40kDa glycoprotein that is over expressed in many cancers including ovarian and mesotheliomas is suggested to play a role in cell survival, proliferation, tumor progression and adherence. However, the biological function of mesothelin is not fully understood as MSLN knockout mice do not present with an abnormal phenotype. Conversely, MSLN has been shown to bind to the ovarian cancer antigen, CA-125, and thought to play a role in the peritoneal diffusion of ovarian tumor cells. Taking into consideration the potential importance of MSLN/CA-125 binding in ovarian tumor metastasis within the peritoneum, MSLN wild type (WT) and knockout (KO) mice were used to explore the role of mesothelin on the susceptibility of ovarian tumor cells to adhere to the mesothelium of the organs in the peritoneal cavity. An ex vivo peritoneal assay, using CA-125 positive human ovarian tumor cells OVCAR8-GFP and peritoneal explants from MSLN WT and KO mice demonstrated a decrease in OVCAR8-GFP cell adhesion to peritoneal tissues from MSLN KO mice compared to MSLN WT mice. Furthermore, allograft tumor studies using MSLN WT and KO mice injected intraperitoneally with fluorescently-tagged syngeneic murine ovarian cancer cells (ID8-RFP) was performed. Disease progression was evaluated post injection by fluorescent in vivo imaging prior to end point dissection (~8 weeks). Abdominal organs were dissected, imaged ex vivo and organ-specific tumor burden was quantified by tumor area. Tumor burden was significantly decreased in the liver and omentum of MSLN KO mice compared to MSLN WT mice. Together, the results demonstrate a loss of mesothelial cell-ovarian tumor cell adhesion in the omentum and peritoneum of mice that do not express MSLN.
Citation Format: Tyvette Hilliard, Kyle Iwamoto, Elizabeth Loughran, Marwa Asem, Yueying Liu, Jing Yang, Laura Tarwater, Yuliya Klymenko, Jeff Johnson, Zonggao Shi, and M. Sharon Stack. IMPACT OF MESOTHELIN EXPRESSION ON THE METASTATIC SUCCESS OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-025.
The Effects of Physical Activity and Body Fat Mass on Colorectal Polyp Recurrence in Patients with Previous Colorectal Cancer
Authors: Park Jihye , Kim Jae Hyun , Lee Hyun Jung , Park Soo Jung , Hong Sung Pil , Cheon Jae Hee , Kim Won Ho , Park Ji Soo , Jeon Justin Y. , Kim Tae Il 
Published: June 2017

Abstract
We aimed to identify the effects of physical activity and body composition on colorectal polyp recurrence in patients with previous colorectal cancer. A total of 300 patients were selected randomly from the colorectal cancer survivor cohort of Severance Hospital (Seoul, Korea). Patients reported various recreational physical activities and received surveillance colonoscopy. Body composition was measured with a body composition analyzer. We compared patients who exercised for at least 1 hour/week (active) with those who exercised less frequently or not at all (sedentary). The active exercise group (n = 203) had a lower recurrence of advanced adenoma than the sedentary group (n = 97; 6.4% vs. 14.4%, P = 0.023). The prevalence of advanced adenoma recurrence decreased in an exercise dose-dependent manner (Ptrend = 0.019). In multivariate logistic analysis, the independent factors associated with advanced polyp recurrence were body fat mass [OR, 7.601; 95% confidence interval (CI), 1.583–36.485; P = 0.011] and active exercise (OR, 0.340; 95% CI, 0.143–0.809; P = 0.015). In Cox proportional hazards models, body fat mass (HR, 5.315; 95% CI, 1.173–24.083; P = 0.030) and active exercise (HR, 0.367; 95% CI, 0.162–0.833; P = 0.017) were the independent factors associated with cumulative advanced adenoma recurrence. In conclusion, exercising for at least 1 hour/week and low body fat mass were found to be related to lower rates of colorectal polyp recurrence in the surveillance of colorectal cancer survivors. Cancer Prev Res; 10(8); 478–84. ©2017 AACR.
Neurons Over Nephrons
Authors: Brinjikji Waleed , Demchuk Andrew M. , Murad Mohammad H. , Rabinstein Alejandro A. , McDonald Robert J. , McDonald Jennifer S. , Kallmes David F. 
Published: June 2017

Background and Purpose—
Because of the perceived risk of contrast-induced acute kidney injury (AKI), many centers require pre-imaging serum creatinine levels, potentially delaying care. We performed a systematic review and meta-analysis evaluating AKI rates in patients with acute ischemic stroke receiving computed tomographic angiography (CTA) and computed tomographic perfusion (CTP).

Methods—
We searched MEDLINE, EMBASE, and the Web of Science through December 2016 for studies reporting on AKI in patients with acute ischemic stroke receiving CTA/CTP. Using a random-effects model, estimates were pooled across studies. Outcomes of interest were (1) the odds of AKI in patients receiving CTA/CTP versus noncontrast computed tomography, (2) overall rate of AKI and hemodialysis in patients with acute ischemic stroke undergoing CTA/CTP, and (3) the odds of CTA/CTP-associated AKI among patients with and without chronic kidney disease.

Results—

Fourteen studies were included (6 case–control studies and 8 single-arm studies) with 5727 CTA/CTP and 981 noncontrast computed tomography patients. In case–control studies, AKI was significantly lower among CTA/CTP patients compared with noncontrast computed tomography patients (odds ratio=0.47; 95% confidence interval=0.33–0.68;
P
<0.01). Adjusting for baseline creatinine, there was no difference in AKI rates between groups (odds ratio=0.34; 95% confidence interval=0.10–1.21). The overall rate of AKI in CTA/CTP patients was 3% (95% confidence interval=2%–4%). The overall rate of hemodialysis in the CTA/CTP group was 0.07% (3 of 4373). There was no difference in AKI among CTA/CTP patients with and without chronic kidney disease (odds ratio=0.63; 95% confidence interval=0.34–1.12).

Conclusions—
Nonrandomized evidence suggests that CTA/CTP are not associated with statistically significant increase in risk of AKI in patients with stroke, even those with known chronic kidney disease.
Ischemic Amnesia
Authors: Michel Patrik , Beaud Valérie , Eskandari Ashraf , Maeder Philippe , Demonet Jean-François , Eskioglou Elissavet 
Published: June 2017

Background and Purpose—
We aimed to describe the frequency and characteristics of acute ischemic stroke and transient ischemic attacks presenting predominantly with amnesia (ischemic amnesia) and to identify clinical clues for differentiating them from transient global amnesia (TGA).

Methods—
We retrospectively analyzed and described all patients presenting with diffusion-weighted imaging magnetic resonance imaging–confirmed acute ischemic stroke/transient ischemic attacks with antero- and retrograde amnesia as the main symptom over a 13.5-year period. We also compared their clinical features and stroke mechanisms with 3804 acute ischemic stroke from our ischemic stroke registry.

Results—
Thirteen ischemic amnesia patients were identified, representing 0.2% of all patients with acute ischemic stroke/transient ischemic attack. In 69% of ischemic amnesia cases, amnesia was transient with a median duration of 5 hours. Ischemia was not considered in 39% of cases. Fifty-four percent of cases were clinically difficult to distinguish from TGA, including 15% who were indistinguishable from TGA. 1.2% of all presumed TGA patients at our center were later found to have ischemic amnesia. Amnesic strokes were more often cardioembolic, multiterritorial, and typically involved the posterior circulation and limbic system. Clinical clues were minor focal neurological signs, higher age, more risk factors, and stroke favoring circumstances. Although all patients were independent at 3 months, 31% had persistent memory problems.

Conclusions—
Amnesia as the main symptom of acute ischemic cerebral events is rare, mostly transient, and easily mistaken for TGA. Although clinical clues are often present, the threshold for performing diffusion-weighted imaging in acute amnesia should be low.
Daily Total Physical Activity and Incident Stroke
Authors: Kubota Yasuhiko , Iso Hiroyasu , Yamagishi Kazumasa , Sawada Norie , Tsugane Shoichiro 
Published: June 2017

Background and Purpose—
There is limited evidence on the association between total physical activity and stroke in Asian populations experiencing a greater burden of hemorrhagic stroke than Western populations. We aimed to understand their optimal level of physical activity for stroke prevention.

Methods—
A total of 74 913 Japanese people 50 to 79 years of age without histories of cardiovascular disease or cancer were followed from 2000 to 2012.

Results—
During the 698 946 person-years of follow-up, we documented a total of 2738 incident cases of stroke, including 1007 hemorrhagic strokes (747 intraparenchymal and 260 subarachnoid hemorrhages) and 1721 ischemic strokes (1206 nonembolic and 515 embolic infarctions). Individuals in the second or third metabolic equivalents of task–hours per day quartile had the lowest risks of total stroke (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.75–0.93), intraparenchymal hemorrhage (HR, 0.79; 95% CI, 0.64–0.97), subarachnoid hemorrhage (HR, 0.78; CI, 0.55–1.11), and nonembolic infarction (HR, 0.78; CI, 0.67–0.92), whereas those in the fourth quartile had the lowest risk of embolic infarction (HR, 0.76; CI, 0.59–0.97). Cubic spline graphs revealed a steep decrease in stroke risk (30% risk reduction) from the lowest level to a plateau at 5 to 10 metabolic equivalents of task–hours per day (50th percentile). The associations of total physical activity level with hemorrhage stroke showed U or J shape, which were because of vigorous-intensity activities, whereas the association with ischemic stroke showed L shape.

Conclusions—
For Japanese people, moderate levels of total physical activity, particularly achieved by moderate-intensity activities, may be optimal for stroke prevention because excessive vigorous-intensity activities might not be beneficial or even disadvantageous for prevention of hemorrhagic stroke.