bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A61: Dissecting the molecular basis of Ewing's sarcoma metastasis
Authors: Choo Sun , Yang Jing 
Published: May 2015

Abstract
Ewing's sarcoma family of tumors is a group of poorly differentiated malignant pediatric cancers of bone and soft tissue. About 25% of patients present with clinically detectable metastases. Despite aggressive therapy, little improvement has been seen in patients with metastatic disease due to the lack of understanding of the molecular pathways that regulate its spread. There has been immunohistologic and gene expression profiling analyses indicating a striking similarity between Ewing's sarcoma and fetal and neuronal tissues. We hypothesize that a group of genes that regulate a specialized group of embryonic stem cells (neural crest cells) are reactivated to allow Ewing's sarcoma cells to metastasize.
We examined primary human Ewing's sarcoma samples to detect the expression of one of those genes, the Twist1 transcription factor. Twenty Ewing's sarcoma samples were strongly positive for Ewing's sarcoma marker CD99, confirming the correct tumor type. Interestingly 88% (8/11) of metastatic Ewing's sarcoma patients had strong nuclear staining of Twist1 by immunohistochemistry (IHC). In contrast, only 17% (1/6) of non-metastatic tumor samples showed positive Twist1 signals, thus indicating that expression of Twist1 is tightly associated with metastasis in Ewing's sarcoma (P &lt;0.05). Notably Twist1 positivity is also an independent prognostic marker for poor survival in this group of patients. 7 out of the 8 (88%) Twist1 positive patients died from disease versus only 2 out of 8 (25%) in the Twist1 negative patients (p &lt; 0.05). In addition we explored PDGFRα as a possible target for therapy given that PDGFRα is a direct transcription target of Twist1. Indeed PDGFRα expression was significantly associated with Twist1 and also tightly linked to survival (P&lt;0.05) in these patients.
In summary, these results suggest that reactivation of the neural crest migration program through Twist1 plays a critical role in promoting metastasis in Ewing's sarcoma. Functional studies on the role of Twist1 and PDGFRα in Ewing's sarcoma metastasis are ongoing and may lead to targeted therapies against this unique developmental pathway to combat Ewing's sarcoma metastasis.
Citation Format: Sun Choo, Jing Yang. Dissecting the molecular basis of Ewing's sarcoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A61.
Abstract A84: Stereotactic injections of primary medulloblastomas as a representative model of the different subgroups for preclinical drug screening
Authors: Krona Cecilia , Dyberg Cecilia , Sandén Emma , Darabi Anna , Wickström Malin , Northcott Paul , Johnsen John Inge , Siesjö Peter 
Published: May 2015

Abstract
Established tumor cell lines are extensively used for screening of novel therapeutic compounds. However, during long-term culturing cells adjust to the conditions and acquire additional genetic aberrations, which may cause them to differ significantly from the original tumor. In vitro conditions may also fail to recapitulate aspects of the tumor microenvironment that may have an impact on cell fate, for example, drug clearance by the circulation, which would lead to renewed cell cycling and the heterogeneity of the tumor cell population versus the homogenous population of cells in culture. Predisposed genetic mouse models more closely recapitulate most aspects of human disease but they usually require complex breeding schemes and may suffer from incomplete tumor penetrance and a variable age of tumor onset.
In order to establish a new medulloblastoma model for therapeutic studies, we have acquired primary cultures of medulloblastoma tumors representing the four different subtypes of medulloblastomas (Wnt, Shh, group 3 and group 4). Cells were grown as neurospheres and characterized regarding stem cell markers and immunological status. Early passages were collected and for each primary line, two NOD scid mice were orthotopically injected with 20.000 and 200.000 cells, respectively. Mice were closely monitored for symptoms of brain tumor burden (weight loss, hunched posture, uncoordinated movement, lethargy, poor balance and/or paralysis) during six months.
Mice injected with cells from the SHH subgroup and group 3 medulloblastomas developed symptoms of brain tumors with a latency of 13-25 weeks. A positive correlation was observed between tumor latency and number of injected cells. Brains were collected and processed for histopathological confirmation of tumor prevalence, whole genome sequencing and gene expression analysis. Neurosphere cultures were also re-established to create a reproducible model for pre-clinical therapeutic trials on human medulloblastoma by serial orthotopic transplantation.
Citation Format: Cecilia Krona, Cecilia Dyberg, Emma Sandén, Anna Darabi, Malin Wickström, Paul Northcott, John Inge Johnsen, Peter Siesjö. Stereotactic injections of primary medulloblastomas as a representative model of the different subgroups for preclinical drug screening. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A84.
Abstract B38: Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes
Authors: Ohira Miki , Li Yuanyuan , Zhou Yong , Li Xiangchun , Gao Zhibo , Tatsuno Kenji , Tsutsumi Shuichi , Yamamoto Shogo , Nakamura Yohko , Kamijo Takehiko , Aburatani Hiroyuki , Nakagawara Akira 
Published: May 2015

Abstract
Neuroblastoma is known to exhibit wide ranges of clinical behavior, from spontaneous regression to highly resistant to chemotherapy. Previously, we have established the risk classification system based on the copy number profiles of the tumor determined by array CGH analysis. The two most major subclasses with aggressive phenotype are P1a (with partial chromosomal gains/losses, MYCN amplification, 1p loss and 17q gain, but no 11q loss) and P3s (with partial chromosomal gains/losses, 11q loss and 17q gain, but no 1p loss nor MYCN amplification), whose 8-year survival rates were 33% and 31%, respectively, in our database. On the other hand, Ss subgroup, categorized as few chromosomal gains/losses, showed favorable prognosis (8-year survival rate was 82%). To determine and compare the spectrum of genetic alterations in each tumor subtype, we have so far conducted whole-exome sequencing of 101 cases (P1a:17, P3s:44, Ss:20, others including metastasized or relapsed:20). On average, P1a and P3s subgroups had approximately 14 and 19 somatic alterations in coding genes, respectively, while Ss had very few alterations with only 1.2. Few recurrent non-silent mutations were found in all subgroups, however, pathway analysis by David with KEGG database indicated that a part of these novel somatic mutations were concentrated in cancer-related signaling pathways, such as those of MAPK (14 genes, adjusted p&lt;0.001) and Wnt (7 genes, p&lt;0.001), significantly in P1a subtype. Ongoing efforts will validate mutation candidates in a larger scale sample set by independent analysis platforms as well as the correlations with prognosis of each tumor subset.
Citation Format: Miki Ohira, Yuanyuan Li, Yong Zhou, Xiangchun Li, Zhibo Gao, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B38.
Abstract B40: MYCN/MYC protein expression in high-MKI (Mitosis-Karyorrhexis Index) neuroblastomas: A report from the Children's Oncology Group
Authors: Wang Larry L. , Teshiba Risa , He Lejian , Naranjo Arlene , London Wendy B. , Gastier-Foster Julie M. , Seeger Robert C. , Cohn Susan L. , Maris John M. , Park Julie R. , Hogarty Michael D. , Shimada Hiroyuki 
Published: May 2015

Abstract
Background: In neuroblastoma (NB), Mitosis-Karyorrhexis Index (MKI; low-L, &lt;100/5,000 cells; intermediate-I, 100-200/5,000 cells; high-H, &gt;200/5,000 cells) is one of the histologic indicators for predicting a patient's clinical outcome. Event-Free Survival (EFS) and Overall Survival (OS) are significantly worse as MKI increases (p&lt;0.0001): 3-year EFS for L-MKI (81.2+1.0%), I-MKI (68.6+1.8%), H-MKI (51.0+2.2%); and 3-year OS for L-MKI (92.0+0.7%), I-MKI (81.0+1.6%), H-MKI (64.4+2.1%). MYCN amplification (MYCN-A) is significantly associated with H-MKI, which indicates markedly increased mitotic (cellular proliferation) and karyorrhectic (cellular death) cells. However, about one-third of H-MKI tumors do not have MYCN-A.
Study design: A total of 4,712 NB cases reviewed by the Children's Oncology Group (COG) Neuroblastoma Pathology Reference Laboratory (Children's Hospital Los Angeles) between 06/18/2001 and 06/06/2013 included 2,595 L-MKI (3% with MYCN-A), 1,197 I-MKI (16% with MYCN-A), and 920 H-MKI (70% with MYCN-A) tumors. In this study, immunohistochemical detection of MYCN and MYC (C-myc) protein was performed on 82 H-MKI tumors (53 with MYCN-A and 29 without MYCN-A).
Results: 50/53 (94%) of H-MKI tumors having MYCN-A were positive for MYCN protein (including one case positive for both MYCN and MYC proteins), and only 3 cases were negative for both proteins immunohistochemically. Among the H-MKI tumors without MYCN-A, 16 cases (55%) showed positive staining for MYC protein, 6 cases (21%) were positive for MYCN protein, 2 cases (7%) were positive for both proteins, and 5 cases (17%) were negative for both proteins.
Conclusions: MYCN-A and subsequent MYCN protein expression are considered as the starting point for leading NB tumors to H-MKI status. However, when MYCN is not amplified, high mitotic/karyorrhectic (M/K) activities in NB tumors are often associated with MYC protein expression. Even some MYCN non-amplified tumors can express MYCN protein, which is associated with H-MKI. There is still a small group of H-MKI tumors whose increased M/K activities are not related to MYCN/MYC protein expression.
Citation Format: Larry L. Wang, Risa Teshiba, Lejian He, Arlene Naranjo, Wendy B. London, Julie M. Gastier-Foster, Robert C. Seeger, Susan L. Cohn, John M. Maris, Julie R. Park, Michael D. Hogarty, Hiroyuki Shimada. MYCN/MYC protein expression in high-MKI (Mitosis-Karyorrhexis Index) neuroblastomas: A report from the Children's Oncology Group. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B40.
Abstract B59: Wild-type ALK and both ALK-R1275Q and ALK-F1174L activating mutations display a strong oncogenic activity in vivo in murine neural crest progenitor cells via cooperation with c-myc
Authors: Mühlethaler-Mottet Annick , Montavon Gisèle , Flahaut Marjorie , Jauquier Nicolas , Joseph Jean-Marc , Delattre Olivier , Sommer Lukas , Janoueix-Lerosey Isabelle , Gross Nicole 
Published: May 2015

Abstract
Neuroblastoma (NB), a neural crest-derived embryonal tumor, is a heterogeneous childhood malignancy that often presents as an incurable disease. The anaplastic lymphoma receptor tyrosine kinase gene (ALK) was shown to be overexpressed, mutated or amplified in the majority of NB. The most common mutation, ALK-F1174L displayed an efficient transforming activity in vivo, and was shown in transgenic mouse models to drive NB formation and to cooperate with MYCN in the oncogenic process. In this project, we aimed at comparing the in vivo oncogenic potential of ALK-wt, with the two most frequent activating mutations ALK-F1174L (only present in sporadic NB), and ALK-R1275Q (present in familial and sporadic NB). Our strategy included the stable expression of ALK-wt and mutated variants into murine neural crest progenitor cells (JoMa1), which are the well-recognized NB progenitors.
In vitro, only ALK-F1174L and ALK-R1275Q conferred an oncogenic potential to JoMa1 cells as measured by clonogenic assays. In contrast, in vivo experiments showed that JoMa1 cells expressing ALK-wt, as well as activating mutations ALK-R1275Q and ALK-F1174L rapidly produced highly aggressive tumors after subcutaneous or orthotopic (adrenal gland) implantations in nude mice. JoMa1-ALK-F1174L cells induced the fastest tumor growth as compared to JoMa1-ALK-R1275Q and JoMa1-ALK-wt cells, revealing the tremendous tumorigenic potential of ALK-F1174L cells. Interestingly, as a result from ALK activation, orthotopic tumors or their derived cell lines strongly upregulated c-myc expression. Moreover, specific ALK inhibition using TAE684, or c-myc inhibition with 10058-F4, completely abrogated the in vitro clonogenic capacity of tumor-derived cell lines. Such observations suggest that the tumorigenic potential of neural crest progenitor cells is strongly dependent on both ALK and c-myc activity.
Our study demonstrates for the first time an oncogenic activity of ALK-R1275Q and ALK-wt when overexpressed in neural crest cells, and reveals the complex interactions between ALK and the myc oncogene family in neural crest cell-derived tumor formation.
Citation Format: Annick Mühlethaler-Mottet, Gisèle Montavon, Marjorie Flahaut, Nicolas Jauquier, Jean-Marc Joseph, Olivier Delattre, Lukas Sommer, Isabelle Janoueix-Lerosey, Nicole Gross. Wild-type ALK and both ALK-R1275Q and ALK-F1174L activating mutations display a strong oncogenic activity in vivo in murine neural crest progenitor cells via cooperation with c-myc. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B59.
Abstract B70: Modification of hematopoietic stem cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy
Authors: Oliveira Satiro N. De , Ryan Christine , Wherley Jennifer , Tu Andy , Elashoff David , Cooper Laurence JN , Hollis Roger P. , Kohn Donald B. 
Published: May 2015

Abstract
Pediatric patients with recurrent B-lineage hematological malignancies have less than 50% of chance of cure, despite intensive therapy. Chimeric Antigen Receptors (CARs) redirect immune cells to tumor-associated antigens. CD19 is proposed as target because its B-lineage restriction and expression in the majority of hematological malignancies. Current clinical trials use CD19-specific CAR-modified T-cells, but the effector cells are only transiently present. The main hypothesis is that modification of hematopoietic stem cells (HSCs) with anti-CD19 CAR will generate persistent anti-leukemic activity through production of multilineage effectors. Gene transfer did not impair HSC differentiation and proliferation when transduced at 1-2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive targets, with second-generation CAR including CD28 domains being more efficient in NK cells. CAR-modified human HSCs engrafted in NSG mice, producing functional cell progenies. Furthermore, ex vivo leukocytes presented antigen-specific target lysis, and animals engrafted with CAR-modified cells presented inhibition or elimination of CD19-positive tumors, and consequent survival advantage. First-generation CAR did not present tumor development inhibition or survival advantage when compared to non-modified HSCs, confirming that the addition of co-stimulatory moieties to the CAR construct is necessary for effectiveness. This approach is untested in cancer immunotherapy, implies the use of a patient's own cells, and can be applied to different cancers just by adjusting the target specificity. It bears the possibility of decreased morbidity and mortality, being desirable for vulnerable populations such as children, and offers alternative treatment for patients with no available HLA-matched sources for bone marrow transplantation, benefiting ethnic minorities.
Citation Format: Satiro N. De Oliveira, Christine Ryan, Jennifer Wherley, Andy Tu, David Elashoff, Laurence JN Cooper, Roger P. Hollis, Donald B. Kohn. Modification of hematopoietic stem cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B70.
Abstract B72: Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01)
Authors: Noesel Max M. van , Kraal Kathelijne CJM , Kraker Jan de , Eck-Smit Berthe LF van , Tytgat Godelieve AM , Caron Huib N. 
Published: May 2015

Abstract
Purpose: Patients with high-risk (HR) neuroblastoma (NBL) have a poor prognosis and new treatment strategies are needed. 131I- Meta-Iodobenzylguanidine (MIBG) therapy alone has a significant antitumor efficacy against NBL. Topotecan (TPT) is a radio-enhancer and can potentiate radiation-induced cytotoxicity and up-regulate the uptake of MIBG in vitro. We designed a clinical study with upfront 131I-MIBG therapy and Topotecan for HR-NBL. We evaluated short term clinical response rate and outcome. Clinical response was scored according to International Neuroblastoma response Criteria (INRC) and Curie score (MIBG) after 2 courses of MIBG/TPT and after induction chemotherapy and HD ASCT. Haematological toxicity and the effect on harvesting/ feasibility performing autologous stem cell transplantation (ASCT) was evaluated. Topoisomerase-1 activity (Topo-1) levels were measured.
Methods: Multi-centre, prospective (window phase II) study performed between 2000-2003 in HR NBL patients treated with 2 cycles of upfront 131I-MIBG therapy followed by the addition of TPT 0.7 mg/m2 for 5 days after each course. Thereafter, patients received 4 courses of VECI chemotherapy, followed by surgery and HD ASCT.
Results: Sixteen patients (10 male), median age 2, 8 yrs. NMYC amplified 8/14 (57%) and LOH1P in 7/15 (47%). Surgery performed in 12/16 (75%) patients. Clinical response after 2x MIBG/TPT 15/16 (94%, VGPR/ PR/ MR), 1 PD; after 4x VECI 11/16 (69%, CR/ VGPR/ PR/MR), 3 PD, 1 death and 1 unknown. More than 50% reduction in MIBG Curie score after 2x MIBG/ TPT and subsequent 4x VECI courses in most cases. Overall outcome 2/16 currently alive. Long term follow up was limited, possibly related to low intensity induction chemotherapy as used in this study. Harvesting of stem cells in 13/16 patients (79%), mean yield 2, 2 CD34 pos/ kg, 9/16 (56%) underwent HD ASCT. Haematological toxicity was limited, median platelet recovery after HD ASCT was 73 days. Topo-1 activity was measured in 10/16 tumors, increased compared to reference level.
Conclusion: Upfront treatment of HR-NBL with MIBG/TPT is feasible and highly effective after 2 courses. The toxicity is limited (haematological). Stem cell harvesting and HD ASCT are manageable.
Citation Format: Max M. van Noesel, Kathelijne CJM Kraal, Jan de Kraker, Berthe LF van Eck-Smit, Godelieve AM Tytgat, Huib N. Caron. Upfront treatment of high-risk neuroblastoma with 131I-MIBG therapy and Topotecan. A phase II pilot window study (AMRO-NB-HR-2000/01). [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B72.
Abstract IA22: Targeting histone modifying enzymes in leukemia
Authors: Armstrong Scott A. 
Published: May 2015

Abstract
Leukemias harboring rearrangements of the MLL gene carry a poor prognosis. Recently, it has become increasingly clear that MLL-fusion proteins induce widespread epigenetic deregulation that may mediate much of their transforming activity. The histone methyltransferase DOT1L, which methylates histone 3 on lysine 79 (H3K79), has received particular attention. Several MLL-fusion proteins physically interact with DOT1L. Genome-wide H3K79 methylation profiles in MLL-rearranged leukemias are abnormal, and can serve to distinguish MLL-rearranged from other types of leukemias. Mechanistic studies have demonstrated that MLL-fusion proteins subvert a normal gene regulatory mechanism through aberrant hyperconversion of H3K79 methylation to higher methylated states at critical oncogenic targets including the HoxA cluster genes and Meis1. Remarkably, genetic inactivation or small molecule inhibition of DOT1L and thus H3K79 methylation affects expression of MLL-target loci and is detrimental to the leukemogenic activity of MLL-rearranged cells, thus demonstrating that transformation in these leukemias is driven by a DOT1L dependent, aberrant epigenetic program. Clinical trials of small molecule DOT1L inhibitors are in phase 1 clinical trials. Recent studies on the roles for DOT1L and H3K79 methylation in MLL-rearranged leukemias will be discussed.
Citation Format: Scott A. Armstrong. Targeting histone modifying enzymes in leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA22.
Abstract IA37: Clinical genomics
Authors: Janeway Katherine A. 
Published: May 2015

Abstract
The genomic features of pediatric malignancies and pediatric-specific issues in clinical investigation pose pediatric-specific challenges with respect to translating genomic discoveries to the clinic. However, through large scale molecular profiling of pediatric tumors, continued coordinated efforts to evaluate novel therapies in the pediatric population, thoughtful phase II and III trial design and continued drug development, molecularly based targeted therapies will become more common in the pediatric oncology clinic in the future. Consequently, it is essential to rigorously evaluate the clinical utility of advanced molecular diagnostics in pediatric oncology and the efficacy of a precision medicine approach to therapy selection. We are conducting a multi-institution clinical tumor profiling study, the iCat1 study evaluating the feasibility of identifying actionable alterations and making individualized cancer therapy recommendations using currently available clinically applicable tumor profiling technologies.
Citation Format: Katherine A. Janeway. Clinical genomics. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA37.