bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 602: Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers
Authors: Zhang Xi , Tang Kai , Hughes Brett , Vasani Sarj , Liu Zhen , Warkiani Majid , Hartel Gunter , Ladwa Rahul , Kenny Liz , Punyadeera Chamindie 
Published: July 2021

Abstract
Background: Metastases remains the major cause of death in head and neck cancer (HNC) patients. Circulating tumour cells (CTCs) that are shed from primary and metastatic sites and circulate in patients' peripheral blood, represent an important window into disease status. Minimally invasive techniques are required to identify at time of diagnosis, which patients will have worse prognosis due to distant relapse.
Method: We collected bloods from treatment naïve, locoregionally advanced HNC patients (n=72) at the time of diagnosis, and CTCs were isolated using a spiral microfluidic device. CTCs were then immobilised onto glass slides and identified by using immunofluorescence staining (Cytokeratin/CD45/DAPI). We then correlated the CTC numbers of each patient to their clinical outcome based on either PET/CT scan and/or clinical assessment after definitive treatment.
Results: CTCs were detected in 39/72 (54%) of patients (ranging from 1-18 CTCs/10 mL blood) at diagnosis. CTC numbers were correlated to TNM staging (p&lt;0.01), especially the Node staging (p&lt;0.01). Patients with ≥2 CTCs at baseline showed significantly worse prognosis than those with no CTCs detected (P&lt;0.001). We also found that baseline CTCs is an independent predictor of the adverse clinical outcome (residual disease, recurrence, and equivocal clinical presentation) even after adjusting to other prognostic factors (hazard ratio=4.613, p&lt;0.05). Patients with CTC cluster had poor prognosis compared to patients with single CTCs.
Conclusion: We were able to predict disease progression based on CTC numbers, thus providing potential additional prognostic information for locally advanced HNC patients. The ability to detect CTCs at diagnosis allows us to stratify the risk in patients as well as to understand the fundamental mechanisms by which CTCs spread. The clinical benefit of establishing the use of CTCs in HNC is likely to translate into better patient selection for treatment intensification and/or de-intensification strategies.
Citation Format: Xi Zhang, Kai Tang, Brett Hughes, Sarj Vasani, Zhen Liu, Majid Warkiani, Gunter Hartel, Rahul Ladwa, Liz Kenny, Chamindie Punyadeera. Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 602.
Abstract 604: PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+ T cell effector responses, in the presence of tumor antigens, in a murine melanoma model
Authors: Kalim Khalid W. , Tahiliani Vikas , Miriyala Jayalakshmi , Dillon Patrick J. , Trinh Anh M. , Chaney Abra N. , Seavey Matthew M. , Dixon Eric P. , Jasuja Rahul R. , Hutchins Jeff T. 
Published: July 2021

Abstract
Tumor cells evolve multiple mechanisms to escape immune surveillance, one of which is to establish a tolerogenic microenvironment by recruiting immune suppressive cell types such as regulatory T cells (Tregs). Tumor Necrosis Factor Receptor Super Family 25 (TNFRSF25), also known as Death Receptor 3 (DR3), is a potent costimulatory molecule and is preferentially expressed by activated and antigen-experienced T cells. PTX-35, a potential first-in-class TNFRSF25 agonist antibody, is currently in a Phase 1 clinical trial in patients with solid tumors. The purpose of this study was to characterize the impact of mouse PTX-35 (mPTX-35) on tumor growth as well as Treg stability and functionality, including propensity of Tregs to be converted to effector CD4+ T cell subtypes. In this murine melanoma model, C57BL/6 mice were subcutaneously injected with B16.F10-OVA tumor cells. Mice were administered various combinations of mPTX-35, a PD-1 inhibitor, and tumor antigens. When mPTX-35 was administered with tumor antigens, we observed: (1) reduction in the suppressive activity of Tregs, as reflected by decreased expression of CD25 and Nrp1 among Tregs in the peripheral blood and CTLA-4 in the tumor; (2) compromised Treg stability and increased Treg plasticity, including an increased percentage of RORγt+Foxp3+ unstable Tregs and increased conversion of Tregs to RORγt+Foxp3- Th17 cells; (3) increased effector IFNγ+ Th1 cells and effector IL17+ Th17 cells in blood and tumor microenvironment; and (4) elevation in effector IFNγ+ CD8+ T cells in the blood. Importantly, these changes in Treg stability and functionality were associated with delayed tumor progression. In conclusion, we demonstrate that mPTX-35, in the presence of tumor antigens, resulted in the reprogramming of the Treg cell phenotype, including reduced suppressive activity of Tregs and increased plasticity towards inflammatory Th1 and Th17 cells. PTX-35 has the potential to improve the efficacy of treatment regimens where tumor antigens are released.
Citation Format: Khalid W. Kalim, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick J. Dillon, Anh M. Trinh, Abra N. Chaney, Matthew M. Seavey, Eric P. Dixon, Rahul R. Jasuja, Jeff T. Hutchins. PTX-35, a potential first-in-class TNFRSF25 agonist, reduced the suppressive activity of regulatory T cells and enhanced CD4+ T cell effector responses, in the presence of tumor antigens, in a murine melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 604.
Abstract 610: Paired alterations of 35-gene expressing profiles before and after neoadjuvant chemoradiation in esophageal squamous cell carcinoma patients impact clinical prognosis
Authors: Chen Yu-Jen , Bhan Prerana , Wu Terry , Chang Hang , Lee Chi-Jung 
Published: July 2021

Abstract
Purpose: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is widely used for treating locally advanced esophageal cancer in the thorax. The aim of this study was to evaluate alterations of the 35-gene expression profiles in irradiated esophageal tissues before and after chemoradiation.
Materials and Methods: A total number of 50 patients with Esophageal squamous cell carcinoma (ESCC) received neoadjuvant CCRT were retrospectively reviewed. The prescribed radiation dose for gross tumor and metastatic lymph nodes or subclinical mucosal/submucosal disease and regional lymphatic basin were 48 Gy and 43.2 Gy, respectively. All patients underwent CCRT using the intensity-modulated radiation therapy in 24 fractions and received concurrent chemotherapy with cisplatin. A 35-gene expression profile derived from reported ESCC-specific next-generation sequencing was performed. Paired 35-gene expression profiles were analyzed using pre-CCRT biopsy and post-CCRT esophagectomy specimens. In vitro validation of differential expression genes by using human ESCC cell lines 81T and TE2 was performed using the same 35-gene panel.
Results: The alterations in mutation of genes between pre-CCRT biopsy and post-CCRT surgical specimens (delta expression profiles) correlated with pathological complete remission, overall survival and progression free survival. Among the delta expression profiles, the most significant alterations with prognostic impact were noted in MYH4 (p.Gln1210fs) and TTN (p.Asp7145His). Mutation of MYH4 (p.Gln1210fs) and TTN (p.Asp7145His) were demonstrated with favorable and unfavorable impact on rate of pathological complete remission, respectively. The mutation of MYH4 was also noted in human ESCC cell lines 81T and TE2 cells.
Conclusion: By using the 35-gene expression profiles, specific mutations correlated to prognosis in esophageal squamous cell carcinoma patients receiving neoadjuvant chemoradiation and esophagectomy were found. The role of MYH4 mutation in treatment outcome and development as therapeutic target of esophageal squamous cell carcinoma remains to be clarified.
Citation Format: Yu-Jen Chen, Prerana Bhan, Terry Wu, Hang Chang, Chi-Jung Lee. Paired alterations of 35-gene expressing profiles before and after neoadjuvant chemoradiation in esophageal squamous cell carcinoma patients impact clinical prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 610.
Abstract 627: Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system
Authors: Lee Sung Hwan , Lee Sunyoung , Lee Ju-Seog 
Published: July 2021

Abstract
Introduction: Even though the 8th edition AJCC cancer staging system for pancreatic cancer has validated major clinicopathologic factors in multiple clinical cohorts, there is still an unmet need for integrative consideration using multi-omics data to stratify the patients with pancreatic cancer elaborately.
Methods: We performed a comprehensive analysis and profiling using genomic, transcriptomic, and proteomic data from TCGA-PAAD and other translational cohorts (4 cohorts, n=340). Molecular features and major subtypes were analyzed mutually with clinical and pathologic factors, especially the 8th AJCC staging system.
Results: Aggressive molecular subtypes, basal-like and squamous subtype, were significantly associated with a higher nodal stage, but tumor size didn't show a clear association with molecular features. The activated stroma of the pancreatic cancer microenvironment was significantly correlated with poor differentiation and large tumor size. The mutational pattern of KRAS and several transcriptomic pathways, such as epithelial-mesenchymal transition and DNA repair, were differently presented in each clinical stage from the 8th AJCC TNM staging system. The optimal algorithm was identified to show significantly higher performance for the prediction for cancer relapse and cancer-specific survival in discovery and validation cohorts. The in-silico prediction for molecular target agents and immunotherapy was performed for final clusters from the optimal stratification system revealed from the integrative analysis.
Conclusions: Our comprehensive multi-omics analysis reveals clear needs for the combination of clinical staging and molecular profiling and provides crucial evidence for precision strategy in patients with resectable pancreatic cancer.
Citation Format: Sung Hwan Lee, Sunyoung Lee, Ju-Seog Lee. Molecular validation of the 8th edition AJCC cancer staging system for resectable pancreatic cancer: Proposal of integrative translational staging system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 627.
Abstract 632: Growth hormone deficiency in childhood germ cell tumor survivors
Authors: Lone Diana W. , Sadak Karim T. , Miller Bradley S. , Hubbard Aubrey K. , Sample Jeannette , Roesler Michelle , Poynter Jenny N. 
Published: July 2021

Abstract
Introduction: Germ cell tumors (GCTs) are a rare heterogenous group of cancers accounting for 3% of childhood cancers and 15% of cancers in adolescents. Cure rates for GCTs exceed 90% and GCTs currently comprise the 3rd largest group of childhood cancer survivors in the United States. Little systematic evidence exists on late effects of cancer treatment in this group. Treatment for GCTs includes some combination of chemotherapy, radiation, and gonadectomy; interventions that place survivors at high risk for developing endocrinopathies. One of the most common endocrinopathies experienced by childhood cancer survivors is growth hormone deficiency (GHD). In this analysis, we evaluated the prevalence of growth hormone deficiency among GCT survivors.
Methods: Participants were previously enrolled in the Germ Cell Tumor Epidemiology Study (GaMETES), which is a case parent triad study conducted using the Children's Oncology Group registry protocols. Data on late effects and outcomes are currently available for a subset of the participants who have provided additional consent for a follow-up study including a self-administered questionnaire and medical record retrieval. GHD was identified via self-report and validated through medical records. Treatment information was abstracted from the medical records.
Results: In this interim analysis, 230 participants completed the self-administered questionnaire, including 61 with ovarian tumors, 40 with testicular tumors, 38 extragonadal tumors, and 92 intracranial tumors. Thirty-six of the participants reported having growth hormone deficiency (GHD), all of whom had intracranial germ cell tumors (iGCTs). Thus, the prevalence of GHD among iGCT survivors was 39.1%. We validated 45 questionnaire responses against chart review of iGCT patients. Among these 45, 24 (53.33%) iGCT survivors had GHD. Participants who were treated with high doses of cranial radiation (&gt;30 Gy) were more likely to have GHD (OR = 2.3, 95% CI 0.4-13.1).
Conclusions: Growth hormone deficiency is highly prevalent in survivors of childhood intracranial germ cell tumors. The increased prevalence is likely related to the propensity for germ cell tumor involvement of the pituitary stalk, chemotherapy and cranial radiation. Exposure to higher cumulative doses of cranial radiation is associated with higher risk for developing growth hormone deficiency.
Citation Format: Diana W. Lone, Karim T. Sadak, Bradley S. Miller, Aubrey K. Hubbard, Jeannette Sample, Michelle Roesler, Jenny N. Poynter. Growth hormone deficiency in childhood germ cell tumor survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 632.
Abstract 635: Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG)
Authors: Borsuk Robyn , Zhou Lanlan , Zhang Yiqun , Prabhu Varun V. , Allen Joshua E. , Tapinos Nikos , Lulla Rishi , El-Deiry Wafik S. 
Published: July 2021

Abstract
ONC201, a first-in-class, small molecule, imipridone therapy, is known to induce apoptosis via upregulation of TNF-related apoptosis inducing ligand (TRAIL) and its proapoptotic death receptor (DR5), independent of p53. Current trials have been exploring ONC201 as a monotherapy or in conjunction with radiotherapy, in treatment of patients with newly diagnosed and refractory diffuse intrinsic pontine gliomas (DIPG), a disease which remains incurable at present. We sought to identify synergy between ONC201 or second generation impridones (ONC206 and ONC212), and other chemotherapeutics with known promising pre-clinical activity against DMGs.
Seven patient derived H3K27M mutant DIPG cell lines (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SUDIPG-27, SU-DIPG-29, SU-DIPG-36, SF8628) were grown in culture and exposed to ONC201, ONC206, or ONC212 either as monotherapy or in combination with other FDA approved chemotherapeutics (histone de-acetylase inhibitors [HDACi], marizomib, etoposide, and temozolomide). Dose dependent response to imipridone therapy was noted in all cell lines, with mean half maximal inhibitory concentration (IC50) of 1.46 µM in ONC201, 0.11 µM in ONC206, and 0.03 µM in ONC212. Synergy was identified via combination studies, with combination indices of &lt;1 indicating some degree of synergy, and &lt;0.5 indicating very strong synergy. We identified strong synergy between ONC201 and HDAC inhibitors: Panobinostat (CI 0.01) and Romidepsin (CI 0.08), with lesser synergy detected with Entinostat (CI 0.59). Romidepsin similarly showed robust synergy with ONC206 (CI 0.1), as did proteasome inhibitor Marizomib (CI 0.1). Combination of ONC212 and Panobinostat demonstrated induction of apoptosis as measured by the induction of poly (ADP-ribose) polymerase (PARP) cleavage. Our results suggest an increased sensitivity of H3K27M DIPG cell lines to second generation imipridones as compared to ONC201. Additionally, we have shown promising synergism between imipridones with Panobinostat or Romidepsin, which should be considered for clinical translation.
Citation Format: Robyn Borsuk, Lanlan Zhou, Yiqun Zhang, Varun V. Prabhu, Joshua E. Allen, Nikos Tapinos, Rishi Lulla, Wafik S. El-Deiry. Response to novel imipridone combination therapies targeting H3K27M mutant diffuse midline glioma (DMG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 635.
Abstract 638: Enhancing the molecular diagnosis, prognosis, and treatment monitoring of retinoblastoma using cell free DNA in aqueous humor
Authors: Xu Liya , Kim Mary E. , Polski Ashley , Prabakar Rishvanth K. , Peng Chen-Ching , Chévez-Barrios Patricia , Kim Jonathan W. , Shah Rachana , Jubran Rima , Kuhn Peter , Cobrinik David , Hicks James , Berry Jesse L. 
Published: July 2021

Abstract
Purpose: All previous studies of retinoblastoma (RB) aqueous humor (AH) analysis for tumor-derived cell-free DNA (cfDNA) have focused on sampling AH from eyes undergoing therapy; results from AH liquid biopsy at the time of diagnosis have not yet been published. Herein, we detail the diagnostic and prognostic genomic biomarkers found in the AH cfDNA from 7 RB eyes at diagnosis, each with longitudinal evaluation of over 12 months in follow-up.
Methods: Subjects included 7 eyes of 6 RB patients who underwent AH sampling at diagnosis. CfDNA from each AH sample was isolated and sequenced to assess genome-wide somatic copy number alterations (SCNAs), followed by targeted resequencing and mutation detection using a custom hybridization panel for RB1 and MYCN. Results were compared to peripheral blood RB1 testing and matched tumor samples, when available. Tumor fraction (TFx) was calculated using ichorCNA.
Results: Five of 7 diagnostic AH samples contained highly recurrent RB SCNAs, 4 with large scale alterations and 1 with a focal RB1 gene deletion. Mutational analysis of AH cfDNA identified pathogenic somatic variants in 5 diagnostic AH samples with high variant allele frequency, while the remaining 2 diagnostic AH samples had either a high TFx from SCNAs or a focal MYCN amplification. Taken together, somatic tumoral genomic information was detected in all 7 diagnostic AH samples. The 2 eyes that required enucleation had poor prognostic biomarkers (chromosome 6p gain and MYCN amplification) present at the time of diagnosis. TFx from longitudinal AH sampling corresponded to treatment response over time in all cases for which sequential AH samples were available.
Conclusions: This study demonstrates that AH sampling at diagnosis is both feasible and safe. Molecular profiling of AH provides a plethora of diagnostic and prognostic information from only a single 0.1 mL AH sample.
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Citation Format: Liya Xu, Mary E. Kim, Ashley Polski, Rishvanth K. Prabakar, Chen-Ching Peng, Patricia Chévez-Barrios, Jonathan W. Kim, Rachana Shah, Rima Jubran, Peter Kuhn, David Cobrinik, James Hicks, Jesse L. Berry. Enhancing the molecular diagnosis, prognosis, and treatment monitoring of retinoblastoma using cell free DNA in aqueous humor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 638.
Abstract 645: Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat
Authors: Pan Qingfei , Zeleke Tizita , Chiuzan Cody , Onishi Maika , Alvarez Mariano , Honan Erin , Yang Min , Chia Pei Ling , Mukhopadhyay Partha , Kelly Sean , Wu Ruby , Fenn Kathleen , Trivedi Meghna , Accordino Melissa , Crew Katherine , Hershman Dawn , Maurer Matthew , Jones Simon , Califano Andrea , Kalinsky Kevin , Yu Jiyang , Silva Jose 
Published: July 2021

Abstract
Despite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients. We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ~3,000 primary human breast cancers showed that ~30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2- disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective, CLIA certified predictive biomarker of ricolinostat sensitivity in multiple human cancers.
Citation Format: Qingfei Pan, Tizita Zeleke, Cody Chiuzan, Maika Onishi, Mariano Alvarez, Erin Honan, Min Yang, Pei Ling Chia, Partha Mukhopadhyay, Sean Kelly, Ruby Wu, Kathleen Fenn, Meghna Trivedi, Melissa Accordino, Katherine Crew, Dawn Hershman, Matthew Maurer, Simon Jones, Andrea Califano, Kevin Kalinsky, Jiyang Yu, Jose Silva. Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 645.