bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA09: Use of novel treatments for childhood ALL
Authors: Gore Lia 
Published: May 2016

Abstract
Overall and disease free survival for childhood acute lymphoblastic leukemia (ALL) has continued to improve such that there are now subsets of patients with ALL who have a greater than 98% chance for cure, while some have significantly poorer outcomes and remain refractory to conventional treatments. Prognostic factors are refined sufficiently to allow risk-directed categorization and disease treatment allocation, which for some patients may mean less intensive therapy and the potential for fewer short- and long-term side effects, while advances in molecular and genomic diagnostics are increasingly being used to consider alterations in primary therapy for higher risk patients. Recent developments in therapies for childhood ALL such as those presented at this meeting have altered the landscape of available options for the treatment of relapsed ALL in particular, and increasingly, practicing pediatric oncologists are challenged to place these new treatments into the context of currently established therapies and prioritize the options for relapsed patients specifically.
Immunotherapy and strategies using chimeric antigen T-cells, virus-specific T-cells, bi-specific antibodies (T-cell engaging and otherwise), and immunotoxins have greatly increased in availability and sophistication, and are now more widely available, with ever-increasing potential applications, although to date, they have not been applied to newly diagnosed patients. Simultaneously, the number of available new therapeutic options is large enough that meaningful clinical trials can be difficult to conduct based on the proportion of agents to the number of available patients eligible for such trials. A pressing challenge to the field is to begin to place these therapies in the context of more conventional approaches to the currently highly successful treatment of ALL for a large majority of affected patients, and to continue to evaluate both the short- and long-term consequences of newer treatments both alone and in combination with other more conventional agents.
Discussion about what constitutes a truly novel therapy and examples of currently available experimental therapies for childhood ALL will be reviewed. The context of these treatments to future strategies and trial opportunities for both single agent and combination explorations will be discussed.
Citation Format: Lia Gore. Use of novel treatments for childhood ALL. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA09.
Abstract IA12: SWI/SNF (BAF) complex mutations in cancer
Authors: Roberts Charles W. M. 
Published: May 2016

Abstract
Data emerging over the last several years implicate the SWI/SNF (BAF) chromatin remodeling complex as a major tumor suppressor as frequent inactivating mutations in at least eight SWI/SNF subunits have been identified in a variety of cancers. These include inactivating mutations of the gene encoding the ARID1A (BAF250a) subunit in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers; and of the BRG1 (SMARCA4) subunit in non-small cell lung cancers, medulloblastomas and ovarian small cell carcinomas. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription.
My laboratory began studying the SWI/SNF complex when the SNF5 (SMARCB1/INI1/BAF47) subunit was first identified as a tumor suppressor over a decade ago when it was found to be recurrently and specifically inactivated in a highly aggressive type of pediatric cancer called malignant rhabdoid tumor. We now study the complex using mouse models, cell lines and primary human tumor samples. Our goals are to elucidate the normal function of the complex, identify the mechanisms by which subunit mutations drive cancer formation, and utilize this insight to identify and develop novel therapeutic approaches. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented.
Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA12.
Abstract IA24: Science of surviving cancer: Lessons learned from our cancer survivors
Authors: Bhatia Smita 
Published: May 2016

Abstract
The 5-year overall survival rate for childhood cancer now exceeds 80%. As a result of this improvement in survival, the number of childhood cancer survivors now exceeds 375,000. The increasing number of long-term survivors is attended by a growing awareness that many will develop health conditions as a direct or an indirect consequence of their cancer therapy. While some of these conditions occur during therapy and persist well after the therapy has been completed (such as steroid-induced osteonecrosis, or alkylating agent /radiation-induced hypogonadism), many outcomes are not evident until 10-20 years later, such as subsequent malignant neoplasms (SMNs) and anthracycline-related late onset congestive heart failure (CHF). Individuals exposed to radiation and chemotherapy are vulnerable to long-lasting organ toxicity. While clear and unambiguous associations exist between therapeutic exposures and specific complications, considerable inter-individual variability is observed in the risk of developing an outcome for any given exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the inter-individual variability. Thus, it becomes imperative to understand the individual variability in: i) the internal dose of the therapeutic agent; ii) the biologically effective dose; iii) the alterations in structure or function of the tissue or organ; and iv) the consequent development of preclinical disease, in order to understand the pathogenesis of therapy-related complications, and also develop a better idea of the individual susceptibility. Over the past decade, there have been several reports describing the role of genetic susceptibility in anthracycline-related CHF, in chemotherapy-related leukemia, radiation-related solid SMNs, and corticosteroid-related osteonecrosis. These studies have varied in their investigative approach – from a candidate gene investigation to a genome-wide association study. Understanding the etiology and pathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life.
Citation Format: Smita Bhatia. Science of surviving cancer: Lessons learned from our cancer survivors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA24.
Abstract IA25: Prevention in survivors: Reducing the “cost” of surviving childhood cancer
Authors: Diller Lisa R. 
Published: May 2016

Abstract
Childhood cancer survivors are at significantly increased risk of treatment-related chronic disease and subsequent malignancy. Preventive intervention and screening can hopefully reduce the morbidity or mortality of these late-occurring illnesses. Screening for secondary cancer based upon prior exposures has been implemented for detection of early radiogenic breast cancers, skin cancers and GI malignancies. In adults without a history of childhood cancer, prevention strategies for diseases such as breast cancer and coronary artery disease have been investigated, but there is little evidence for the use of population-based strategies in childhood cancer survivors. We will review the role of primary and secondary prevention in childhood cancer patients and survivors. How have reduction of therapy studies reduced risk of late sequelae? What prevention interventions have been studied in survivors and what is the ongoing research in survivors? Data from studies of breast cancer screening with MRI and prevention with tamoxifen will be presented. Can we draw experience in prevention in other high-risk groups to apply to childhood cancer survivors? We will present results of our unique survivorship Markov model, which can help estimate the impact of screening strategies on outcome. Finally, prevention strategies carry potential risk – how do we help patients make decisions and help them understand risk?
Citation Format: Lisa R. Diller. Prevention in survivors: Reducing the “cost” of surviving childhood cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA25.
Abstract IA26: Oncogenic mechanisms in diffuse intrinsic pontine gliomas
Authors: Silveira Andre B. , Kasper Lawryn H. , Larson Jon D. , Zhu Xiaoyan , Diaz Alexander K. , Baker Suzanne J. 
Published: May 2016

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating disease with no effective cures. DIPG arises in the brainstem and is found almost exclusively in children. Mutations in canonical cancer signalling pathways including the RTK/RAS/PI3K pathway, the Tp53 pathway, and the CDK4/6 G1 checkpoint occur in DIPGs, targeting different effectors within these pathways and resulting in significant genetic heterogeneity between tumors. However, genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. Recurrent mutations of the BMP receptor ACVR1/ALK2 are found in 25-30% of DIPGs, and are further restricted to the youngest patients, highlighting critical connections between development and gliomagenesis. The molecular hallmark of DIPGs is frequent recurrent somatic mutation in histone H3. Mutually exclusive somatic heterozygous H3F3A or HIST1H3B mutations encoding a K27M variant of histone H3.3 or H3.1, respectively, are found in nearly 80 percent of DIPGs. These recurrent mutations provide clear evidence of an important role for chromatin regulation in DIPG disease pathogenesis, and present a unifying molecular mechanism driving DIPG. We have evaluated the contribution of H3.3 K27M mutation to DIPG tumor growth in vitro to gain insights into molecular mechanisms of oncogenic activity, and to assess the potential of histone H3 mutation as a therapeutic sensitivity in this incurable brain tumor.
Citation Format: Andre B. Silveira, Lawryn H. Kasper, Jon D. Larson, Xiaoyan Zhu, Alexander K. Diaz, Suzanne J. Baker. Oncogenic mechanisms in diffuse intrinsic pontine gliomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA26.
Abstract IA28: New targeted approaches for high-risk pediatric malignancies
Authors: Stegmaier Kimberly 
Published: May 2016

Abstract
While significant progress has been made in treating many pediatric malignancies, cancer remains the leading cause of death from disease in children. A number of childhood cancer subtypes remain particularly recalcitrant to dose-intensified cytotoxic treatment suggesting that new approaches are needed. Initial optimism that massively parallel sequencing efforts would reveal imminently targetable lesions has been tempered by a major finding that pediatric cancers often have simple genomes. While a signature mutation is frequently present, the product is often considered a difficult drug target, such as an aberrant transcription factor. Thus, the hope that cancer can be treated with combinations of drugs targeting specific gene mutations is unlikely to be imminently viable for most pediatric cancers.
We hypothesized that while there is a notable paucity of events in easily druggable enzymes, a small number of sentinel lesions in an otherwise quiet genome may enable the discovery of synthetic lethal relationships with these key genetic events. Thus, we are applying unbiased approaches to identify key dependencies in pediatric cancers using functional genomic screening (shRNA and CRISPR) and chemical genomic screening. The primary goal is to connect key genetic lesions or disease lineages to new gene targets or small-molecule perturbations in the highest risk subtypes of pediatric cancers. Illustrative examples of our early findings will be presented.
Citation Format: Kimberly Stegmaier. New targeted approaches for high-risk pediatric malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA28.
Abstract BL2: Lessons learned from an expedition exploring the world of HER2 positive breast cancer
Authors: Piccart M 
Published: May 2016

Abstract
HER2 positive breast cancer (BC) is often cited as a model of “treatment individualization”.
This presentation will attempt to review the biomarker research efforts for this disease, with a special focus on the work coordinated by the Institut Jules Bordet in the advanced setting and the work of the Breast International Group (BIG) in the adjuvant setting.
Biomarker (BM) exploration in the context of the CLEOPATRA and EMILIA trials has highlighted the poor prognosis associated with PiK3CA mutations, but has failed to identify any predictive BM beyond HER2. Our group, in collaboration with Dutch cancer centers, has prospectively “imaged” 57 patients under T-DM1 treatment using both “target imaging” (trastuzumab-zirconium PET) and FDG-PET: 4 imaging patterns have emerged, providing a striking illustration of advanced disease heterogeneity. Ongoing work will confirm whether these molecular imaging patterns can help to refine the selection of anti-HER2 therapies and, more specifically, support early discontinuation of expensive drug treatment that is unlikely to benefit patients.
The translational research programs of BIG in the context of its (neo)adjuvant trials for HER2-positive BC will be reviewed and put into the context of findings by other researchers as well as the real needs of patients, which include the following: Can aggressive chemotherapy be avoided ? Can duration of treatment be shortened? Who does not need treatment “escalation”?
Citation Format: Piccart M. Lessons learned from an expedition exploring the world of HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BL2.
Abstract BS2-2: Roles of epigenetic regulation in breast cancer development
Authors: Green MR 
Published: May 2016

Abstract
Changes to the genomic DNA sequence, called mutations, are known to play a critical role in the development of cancer. However, increasing evidence indicates that epigenetic changes (heritable cellular changes in gene expression that do not involve alterations in the DNA sequence) also make important contributions to tumorigenesis. For example, promoter hypermethylation plays a major role in cancer through transcriptional silencing of critical growth regulators such as tumor suppressor genes. Other chromatin modifications, such as histone ubiquitination, methylation and acetylation, affect local chromatin structure and regulate gene transcription. Using genome-wide RNA interference screens, we are uncovering epigenetic modulators that play important roles in breast cancer development and progression. The results of these studies are expected to shed light on the role of epigenetic regulation in breast cancer, and suggest new therapeutic approaches.
Citation Format: Green MR. Roles of epigenetic regulation in breast cancer development. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BS2-2.
Abstract ES3-3: Post-mastectomy breast reconstruction: defining the effects of adjuvant treatment modalities on surgical outcomes
Authors: Sbitany H 
Published: May 2016

Abstract
Post-mastectomy breast reconstruction is routinely offered immediately at the time of mastectomy, and can be performed using prosthetic or autologous techniques. Successful surgical outcomes are routine with these procedures, but can be complicated when adjuvant treatment modalities for breast cancer are employed. The most common adjuvant treatments effecting outcomes in post-mastectomy breast reconstruction are radiation, chemotherapy/hormonal therapy, and axillary lymph node dissection.
Adjuvant radiation therapy has been shown to increase the complication rate in prosthetic breast reconstruction, specifically with increased rates of implant infection (22%, p=0.0), full-thickness mastectomy skin necrosis (11.5%, p=.001), and expander/implant removal (17.7%, p=0.0). Such complication rates are improvements over earlier reports, likely due to altered incision placement in nipple sparing mastectomy to the periareolar area, waiting at least 6 months following radiation completion prior to implant exchange, and the use of acellular dermal matrices (shown on multivariate analysis to reduce explantation rates in setting of radiation). With autologous breast reconstruction, adjuvant radiation has been shown to increase rates of volume flap volume loss (19.75%, p=.0001), but not flap loss rates (1.23%, p=1).
The use of adjuvant chemotherapy and hormonal therapy has not been shown to negatively impact outcomes in prosthetic breast reconstruction, to any statistically significant amount. This includes tamoxifen and herceptin therapy. Similarly, the use of hormonal therapy does not significantly effect overall outcomes in autologous breast reconstruction.
The use of axillary lymph node dissection has been shown to have a significant negative impact on outcomes in prosthetic breast reconstruction, compared to sentinel lymph node biopsy. On multivariate analysis, axillary lymph node dissection increased rates of breast implant loss (RR 2.0, p=.021), relative to sentinel lymph node biopsy. This is due to the decreased lymphatic drainage of remaining breast tissue, and resultant increase in infection and implant loss.
Citation Format: Sbitany H. Post-mastectomy breast reconstruction: defining the effects of adjuvant treatment modalities on surgical outcomes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES3-3.
Abstract ES7-3: Adjuvant endocrine therapy: Is the price of forever too high?
Authors: Niravath P 
Published: May 2016

Abstract
Over the past several years, new data has emerged which shows the added benefit of more aggressive endocrine therapy for both pre- and post- menopausal women. With increasing use of ovarian suppression in pre-menopausal women and extended adjuvant endocrine therapy across the board, we are seeing subsequent increased toxicity. While these more intensive treatments do offer benefit in certain high-risk populations, they can also significantly decrease quality of life for many women. This talk will discuss how to carefully weigh the risks and benefits of an increasingly aggressive endocrine therapy approach for each patient. We will also discuss how to tailor treatment options to the individual patient and her cancer.
Citation Format: Niravath P. Adjuvant endocrine therapy: Is the price of forever too high?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES7-3.
Abstract ES9-1: Role for IGF/Insulin signaling in breast cancer
Authors: Yee D 
Published: May 2016

Abstract
Because insulin regulates glucose homeostasis, there has been extensive study into the molecular mechanisms of action of the insulin signaling system. Besides insulin, additional ligands, insulin-like growth factor (IGF) – I and –II and specific receptors for these ligands regulate cellular biology. The receptors share a similar structure and function. Once ligand binds the extracellular domain, a conformational change occurs allowing autophosphorylation of the intracellular tyrosine kinase domains and subsequent activation of multiple signaling pathways that ultimately result in cellular glucose uptake. Type 2 diabetes mellitus (T2D) results from deficient insulin receptor (InsR) signaling and subsequent elevation of serum glucose with compensatory attempt at regulating this pathophysiology by increased insulin production by the pancreas. While the etiology of T2D is complex and multi-factorial, obesity and insulin resistance are epidemiologically and mechanistically linked. Insulin was one of the first peptide growth factors known to stimulate breast cancer proliferation. Epidemiological data link obesity, metabolic syndrome (hyperinsulinemia), and elevated levels of IGFs to breast cancer risk and poor outcome for women diagnosed with breast cancer. These data, in part, led to the development of multiple targeted therapies for breast cancer. Receptor targeting of IGF-receptor signaling was not successful in hormone receptor (HR) positive breast cancers possibly because drugs designed to target this receptor disrupted the negative feedback of this endocrine system and resulted in the elevation of serum insulin levels. Since InsR was not affected by anti-IGF receptor drugs, the potential that InsR was stimulated by these drug treatments could explain their failure. In contrast to receptor targeting strategies, the inhibition of downstream signaling pathways, such as mTORC1, have been successful in HR-positive breast cancer. Preclinical and clinical data have revealed complex intracellular and endocrine feedback pathways that affect the ability of any single targeted drug to effectively disrupt signals from this ligand-receptor family. This session will discuss combination strategies based on clinical and preclinical studies that could translate into effective drug therapies to disrupt this signaling system.
Citation Format: Yee D. Role for IGF/Insulin signaling in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-1.