bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of gated FDG PET/CT on the staging of patients with suspected or proven newly diagnosed advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer: results from a non-randomized, phase II clinical trial
Authors: Virili Florencia , Obermair Andreas , Sanjida Saira , Nicklin James L , Garrett Andrea , Land Russell , Tang Amy , Campbell Louise , Gebski Val , Thomas Paul 
Published: September 2024

ObjectiveImaging for staging ovarian cancer is important to determine the extent of disease. The primary objective of this study was to compare gated 18F-fluorodeoxyglucose positron emission tomography coupled with computed tomography (FDG PET/CT) and standard CT scan with intravenous contrast to diagnose thoracic involvement in patients with advanced ovarian cancer prior to treatment. The secondary objective was to estimate changes in the International Federation of Gynecology and Obstetrics (FIGO) stage and clinical management resulting from gated PET/CT.MethodsThe IMAGE trial is a non-randomized phase II clinical trial comparing standard CT scanning with gated PET/CT in diagnosing thoracic involvement in a non-selected group of patients with suspected ovarian cancer on a contrast CT scan. Three sets of PET images were obtained comprising an ungated 2 min whole body image, a static 7.5 min image of the upper abdomen and thorax, and a gated end-expiratory image over the upper abdomen and thorax. Images were evaluated for specificity, sensitivity, diagnostic accuracy, and the proportion of patients with changes in FIGO stage and subsequent clinical management was compared between imaging techniques.ResultsA total of 84 patients were enrolled based on a standard CT scan, 67 of whom were eligible for gated PET/CT scans. Diagnostic accuracy with gated PET/CT was more than 80% for lesions in lung, liver, extra-abdominal sites, and pleura, but less than 50% for extra-abdominal lymph nodes. Compared with CT scan at baseline, 46% of patients who had 7.5 min gated PET/CT had disease upstaged from stage III to IV, and 8% had disease downstaged from stage IV to III. However, this led to a change of management in only 5% of patients.ConclusionsGated PET/CT enables upstaging; however, in our institution it altered clinical management only in a minority of patients.Trial registration numberNCT02258165.
Prognosis prediction and immunotherapy optimisation for cryptogenic new-onset refractory status epilepticus
Authors: Jang Yoonhyuk , Ahn Soo Hyun , Park Kyung-Il , Jang Bum-Sup , Lee Han Sang , Bae Jae-Han , Lee Yoonkyung , Sunwoo Jun-Sang , Jun Jin-Sun , Kim Keun Tae , Mon Su Yee , You Ji Hye , Kim Tae-Joon , Shin Hyunsuk , Han Dohyun , Cho Yong Won , Dubey Divyanshu , Chu Kon , Lee Sang Kun , Lee Soon-Tae 
Published: September 2024

BackgroundCryptogenic new-onset refractory status epilepticus (cNORSE) currently lacks comprehensive knowledge regarding its clinical dynamics, prognostic factors and treatment guidance. Here we present the longitudinal clinical profiles, predictive factors for outcomes and the optimal duration of immunotherapy in patients with cNORSE.MethodsThis retrospective secondary endpoint analysis investigated patients with cNORSE identified from a prospective autoimmune encephalitis cohort at a national referral centre in Korea. The main outcomes included longitudinal functional scales, seizure frequency and the number of antiseizure medications. Measures encompassed NORSE-related clinical parameters such as the duration of unconsciousness, immunotherapy profiles, cytokine/chemokine analysis, and serial MRI scans.ResultsA total of 74 patients with cNORSE were finally analysed (mean age: 38.0±18.2; 36 (48.6%) male). All patients received first-line immunotherapy, and 91.9% (68/74) received second-line immunotherapy. A total of 83.8% (62/74) regained consciousness within a median duration of 30 days (14–56), and 50% (31/62) achieved good outcome (mRS ≤2) at 2 years. Poor 1-year outcomes (mRS ≥3) were predicted by the presence of mesial temporal lobe (mTL) and extra-mTL lesions at 3-month MRI, and prolonged unconsciousness (≥60 days). Those with mTL atrophy exhibited a higher seizure burden post-NORSE. The optimal duration of immunotherapy appeared to be between 18 weeks and 1-year post-NORSE onset.ConclusionsThis study elucidates longitudinal clinical dynamics, functional outcomes, prognostic factors and immunotherapy response in patients with cNORSE. These findings might contribute to a more standardised understanding and clinical decision-making for cNORSE.
Abstract A010 The role of TP53 on transposable elements in pediatric cancer
Authors: Laverty Brianne , Yadahalli Shilpa , Subasri Vallijah , Malkin David 
Published: September 2024

Abstract
Background: Transposable elements (TEs) are dynamic repetitive regions which generate mutations and structural variants. TP53 plays a crucial role in suppressing TE movement to maintain genomic stability. The relationship between TP53 and TEs has been extensively studied in tumours, but not the germline. Individuals with germline TP53 pathogenic variants have Li-Fraumeni Syndrome (LFS), a cancer predisposition syndrome with a high lifetime risk of cancer in various tissues. This study aims to characterize the TE landscape in individuals with Li-Fraumeni Syndrome and determine how this contributes to their increased cancer risk. Methods: MELT and xTea were used to identify TEs in children with (n=48) or without (n=198) a germline TP53 variant. TE calls were merged with SURVIVOR and variants were annotated with AnnotSV. To assess the influence of TP53 on TE location, we quantified TEs across genomic windows and identified the top 100 significantly different regions with the Mann-Whitney U test, adjusting for multiple comparisons. We used these regions to develop a gradient-boosted tree model with 5-fold cross-validation to predict TP53 status. Results: Individuals with germline TP53 variants harboured significantly fewer ALU and LINE1 elements in their germline genome compared to the control dataset (p&lt;0.001). The phenomenon was consistent across chromosomes and significant in chromosomes 5 and 11 (FDR&lt;0.05). A gradient-boosted tree model was able to differentiate patients with and without a germline TP53 variant with an AUPRC of 0.77 on an unseen test set. Conclusion: Germline TP53 variants may effect the frequency and location of germline TE insertions, which may influence nearby genomic variations and lead to cancer development. Analyzing TEs in individuals with LFS will enhance our understanding of accelerated cancer development in these patients, informing future research for diagnostic and therapeutic approaches.
Citation Format: Brianne Laverty, Shilpa Yadahalli, Vallijah Subasri, David Malkin. The role of TP53 on transposable elements in pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A010.
Abstract A029 Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis
Authors: Kohrn Rachael , Ohm Joyce 
Published: September 2024

Abstract
Humans are exposed to a variety of environmental toxicants which have been implicated in contributing to cancer development. A possible explanation for this link is that adaptive epigenetic changes occur in stem cell populations upon toxicant exposure. These cells are particularly vulnerable during developmental stages, leading to abnormal gene expression later in life. Environmental exposures have been associated with the initiation of sarcoma development. This study will focus on Ewing Sarcoma (ES), as this malignancy has a low mutational burden relative to other cancer types and is thought to be linked to agricultural chemicals. We are also focusing on stromal antigen 2 (STAG2), which is found to be frequently mutated in ES in addition to multiple other tumor types. Patients with STAG2-mutated ES have higher rates of metastatic disease and worse outcomes, but the reason for this remains poorly understood. STAG2 plays a role in the regulation of genomic organization, DNA repair, and modulation of replication stress (RS). It has also been shown that STAG2 loss may lead to dysregulation of the cGAS-STING pathway, which is critical for tumor immunosurveillance. We are testing the effects of environmental toxicants in mesenchymal stem cells (MSCs), the putative cell of origin for ES and many other sarcomas. We have successfully used CRISPR/Cas9 to generate STAG2 knockout MSCs. With this model, we are testing the effects of STAG2 loss and toxicant exposure on levels of RS, epigenomic instability, and innate immune suppression in MSCs. Our results indicate that these toxicants alter the cell cycle dynamics of MSCs, and that these alterations change depending on STAG2 status. We have also observed changes in the DNA damage response of STAG2-mutant MSCs when exposed to environmental toxicants. Interestingly, effects were seen even at sub-lethal doses that may reflect common, low-level exposures. We believe that our data will contribute to the understanding of the mechanism by which environmental toxicants facilitate malignant transformation of Ewing sarcoma and other pediatric sarcomas.
Citation Format: Rachael Kohrn, Joyce Ohm. Investigating the role of environmental toxicant exposures and STAG2 loss in sarcomagenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A029.
Abstract A066 Acquired resistance to temozolomide in the Th-MYCN mouse as a clinically-relevant platform to evaluate novel therapeutic strategies against high-risk neuroblastoma
Authors: Poon Evon , Liang Tong , Barone Giuseppe , Costa Barbara M. , Heuss Sara , Robinson Simon P. , Lin Charles , Workman Paul , Jamin Yann , Chesler Louis 
Published: September 2024

Abstract
Advances in preclinical models that recapitulate chemorefractory and relapsed disease are needed to better predict the efficacy of an expanding and promising armamentarium of drug candidates being tested in early-phase pediatric clinical trials. Here, we used longitudinal magnetic resonance imaging to design an individualized, dose-escalating treatment regimen that induces evolution of neuroblastoma in the Th-MYCN genetically-engineered mouse model, concomitant with the acquisition of resistance to temozolomide, a standard chemotherapy used in treatment of refractory, relapsed neuroblastoma patients within European early-phase clinical trials. MRI longitudinally identified the development of intra-tumoral heterogeneity. Molecular profiling of expanding, treatment-refractory regions identified prominent up-regulation of the nor-adrenergic core regulatory signature and deregulation of the CDK2 pathway. Treatment with a CDK2/9 inhibitor led to significant response and an overall survival benefit in temozolomide-resistant Th-MYCN tumors and allografts generated from these resistant tumours. These findings demonstrate the utility of genetically-engineered mouse models as platforms to dissect the evolution of chemoresistance in neuroblastoma and they provide a mechanistic rationale to support the evaluation of CDK2/9 in ongoing paediatric phase I studies of chemotherapy combined with temozolomide in relapsed, treatment refractory neuroblastoma patients.
Citation Format: Evon Poon, Tong Liang, Giuseppe Barone, Barbara M. Costa, Sara Heuss, Simon P. Robinson, Charles Lin, Paul Workman, Yann Jamin, Louis Chesler. Acquired resistance to temozolomide in the Th-MYCN mouse as a clinically-relevant platform to evaluate novel therapeutic strategies against high-risk neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A066.
Abstract A072 The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma
Authors: Wang Yueyang , Yang Qiqi , Yan Chuan , Langenau David M. 
Published: September 2024

Abstract
Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for adolescent rhabdomyosarcoma (RMS) muscle cancers. Unfortunately, resistance to OT has been reported in other cancers, with no counterstrategies available. Using preclinical mouse xenograft experiments, we show that OT is effective at curbing RMS growth, yet a subset of tumors develop resistance that is associated with transcriptomic changes that occur in the absence of recurrent genomic mutation. Importantly, a vast majority of resistant RMS models upregulate the PIK3CA/AKT pathway, which in turn activates NRF2 transcription factor phosphorylation and subsequent transcriptional expression of multidrug resistance ABC transport proteins that rapidly efflux drugs from cells. Using dynamic real-time imaging of tumor growth and assessing drug responses at single-cell resolution in human cell line models, we found that the PIK3CA inhibitor alpelisib re-sensitized resistant RMS cells to OT therapy by suppressing the expression of ABC transport proteins. Excitingly, RMS uses the same PIK3CA/AKT pathway activation to drive resistance to standard-of-care combination therapy vincristine, actinomycin D, and cyclophosphamide (VAC) and the combination of OT + alpelisib effectively killed VAC-resistant RMS. Alpelisib also re-sensitized resistant RMS to chemotherapy in preclinical xenograft mouse models resulting in reduced tumor burden and extended disease-free survival. Our work defines a common resistance pathway in RMS and has credentialled a new preclinical strategy to kill therapy-resistant RMS.
Citation Format: Yueyang Wang, Qiqi Yang, Chuan Yan, David M. Langenau. The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A072.
Abstract A081 Biomarker-driven targeting of NAD metabolism in rhabdomyosarcoma
Authors: Vasquez Juan C. , Bhardwaj Prateek , Zhao Sophia , Noronha Katelyn , Lucas Karlie , Sundaram Ranjini , Heer Collin , Morotti Raffaella , Spurrier Josh , Bindra Ranjit S 
Published: September 2024

Abstract
Introduction/Background: New treatments are needed to improve survival in rhabdomyosarcoma (RMS). Cells primarily synthesize nicotinamide adenine dinucleotide (NAD+) through the Preiss-Handler and Salvage pathways driven by nicotinic acid phosphoribosyltransferase (NAPRT) and nicotinamide phosphoribosyltransferase (NAMPT), respectively. NAMPT inhibitors (NAMPTi) have been tested in clinical trials, but their efficacy has been limited by lack of appropriate biomarkers for patient selection. Here, we sought to determine if RMS harbors NAPRT silencing that confers a synthetic lethal interaction with NAMPTi. Methods: NAPRT expression was evaluated by immunohistochemistry (IHC) in human tumor samples. In vitro cell viability assays were performed in RMS cell lines using a panel of NAMPT inhibitors. RMS cells isogenic for NAPRT expression were generated via overexpression or CRISPR/Cas9 KO. For in vivo experiments, orthotopic tumor-bearing mice were treated with vehicle control or OT-82 at 25 mg/kg/dose by oral gavage with or without nicotinic acid (NA) at 25 mg/kg/dose once daily for 3 days per week. Results: In vitro, NAPRT negative isogenic RMS cells showed an exquisite sensitivity to a panel of NAMPT inhibitors. When NA was supplemented to model physiologic conditions, NAPRT+ cells were rescuved while cells harboring loss of NAPRT remained sensitive. In vivo, NAMPTi treatment induced significant tumor regression and improved survival in a NAPRT null RMS xenograft model even in the presence of NA, while NAPRT+ tumors did not response to NAMPTi when combined with NA supplementation. IHC staining in a collection of RMS tissue microarrays obtained from the Children’s Oncology Group demonstrated loss of NAPRT protein expression in roughly 25% of tumors.Conclusion: Overall, these data suggest that NAPRT loss may serve as a therapeutic target in RMS by inducing a synthetic lethal interaction with NAD+ depleting agents. Future studies will determine if NA supplementation can mitigate toxicity and widen the therapeutic index, paving the way for the development of biomarker-driven clinical trials in RMS.
Citation Format: Juan C. Vasquez, Prateek Bhardwaj, Sophia Zhao, Katelyn Noronha, Karlie Lucas, Ranjini Sundaram, Collin Heer, Raffaella Morotti, Josh Spurrier, Ranjit S Bindra. Biomarker-driven targeting of NAD metabolism in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A081.
Abstract B040: Rural-urban differences in multiple symptoms occurrence in pediatric cancer survivors after treatment completion in Nebraska, United States
Authors: Napit Krishtee , Coulter Don , Cordts Katrina , Dai Daisy , Farazi Evi , Watanabe-Galloway Shinobu 
Published: September 2024

Abstract
Background Pediatric cancer is the leading cause of death by disease among children. With advanced treatments, survivors are living longer. However, they often experience multiple symptoms even after the treatment completion. Little is known about whether rural-urban residences are associated with multiple symptoms occurrence in pediatric cancer survivors. Methods We conducted a cross-sectional study of 130 pediatric cancer survivors aged 10-25 who completed treatment within eight years from 2 major hospitals in Nebraska. We used a survey to collect data during their hospital visit and the validated Memorial Symptom Assessment Scale tool to collect information on 30 symptoms. We used the PedsQoL instrument to measure the quality of life. We conducted a multiple linear regression model to find the association between rurality and multiple symptoms and to identify factors associated with multiple symptoms at a level of significance with a p-value of less than 0.05 and an adjusted beta coefficient. Results The mean age of participants was 15.00, the mean year since diagnosis and treatment completion was 4.52 and 2.92, respectively, and the mean number of symptoms was 6.18.Difficulty concentrating (49.23%), lack of energy (46.92%), and feeling drowsy (46.92%) were the most common symptoms. The mean total quality of life score was 82.16 out of 100. In the unadjusted model, the association of residence and multiple symptoms was not found to be significant, but when adjusted for possible confounders such as age, race, ethnicity, education, diagnosis, body mass index, health-related quality of life, the association was found to be significant indicating there are a higher number of symptoms in pediatric cancer survivors residing in rural areas compared to urban areas. Quality of life is also poorer when the number of symptoms is higher. Conclusion Even after the treatment completion, multiple symptoms occur in pediatric cancer survivors, and the number of symptoms is higher for those residing in rural areas.Further exploration is needed because of the higher number of symptoms in those residing in rural areas. The association of multiple symptoms with other neighborhood-level socio-demographic indices, such as the area deprivation index, should also be assessed.
Citation Format: Krishtee Napit, Don Coulter, Katrina Cordts, Daisy Dai, Evi Farazi, Shinobu Watanabe-Galloway. Rural-urban differences in multiple symptoms occurrence in pediatric cancer survivors after treatment completion in Nebraska, United States [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B040.
Abstract B042: Socioeconomic and racial disparities in pediatric cancer outcomes in the Ghanaian health sector: Challenges and strategies for equitable care
Authors: Agyapomaa Mavis 
Published: September 2024

Abstract
Objectives This study aims to investigate the socioeconomic and racial disparities in pediatric cancer outcomes within the Ghanaian health sector. The objectives are to identify the specific challenges faced by different socioeconomic and racial groups, assess the impact of these disparities on diagnosis and treatment outcomes, and propose strategies for achieving more equitable care for pediatric cancer patients in Ghana. Methods A mixed-methods approach was employed, combining quantitative analysis of patient data from national cancer registries and hospitals with qualitative interviews of healthcare providers and affected families. The quantitative component focused on variables such as socioeconomic status, race, stage of cancer at diagnosis, treatment received, and survival rates. The qualitative component explored personal experiences, barriers to care, and perceptions of the healthcare system. Data were collected from multiple regions to ensure a representative sample of the diverse population in Ghana. Results The study found significant disparities in pediatric cancer outcomes based on socioeconomic status and race. Children from lower socioeconomic backgrounds and minority racial groups were more likely to be diagnosed at later stages and had lower survival rates compared to their higher-income and majority-race counterparts. Key challenges identified included limited access to specialized oncology care, financial barriers, inadequate health insurance coverage, and cultural beliefs affecting treatment-seeking behavior. Additionally, there was a shortage of trained healthcare professionals and insufficient infrastructure in rural areas. Conclusion Socioeconomic and racial disparities significantly impact pediatric cancer outcomes in Ghana. Addressing these disparities requires a multifaceted approach, including policy interventions to improve healthcare access and affordability, targeted outreach programs to educate communities, and investment in healthcare infrastructure and workforce training. Implementing these strategies can promote more equitable care and improve survival rates for all pediatric cancer patients in Ghana. Collaboration between government, healthcare providers, and non-governmental organizations is essential to overcome these challenges and ensure that every child has the opportunity for a healthy future.
Citation Format: Mavis Agyapomaa. Socioeconomic and racial disparities in pediatric cancer outcomes in the Ghanaian health sector: Challenges and strategies for equitable care [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B042.