bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective evaluation of pre-treatment ctDNA burden in localized osteosarcoma to identify patients with inferior outcomes: A report from the LEOPARD study.
Authors: Shulman David Stephen , Klega Kelly S. , Chen Nan , Gohn Elliot , Henry Donovan , Choy Edwin , Cash Thomas , Schultz Kris Ann Pinekenstein , Mascarenhas Leo , Bagatell Rochelle , Turpin Brian , Setty Bhuvana , DeNardo Bradley , Hawkins Douglas S. , Bishop Michael W. , Shah Avanthi T , Maese Luke Devon , London Wendy B , DuBois Steven G. , Crompton Brian D. 
Published: June 2024

11510 Background: Prior retrospective analyses demonstrated that elevated pre-treatment ctDNA was associated with poor outcomes in newly diagnosed localized osteosarcoma. The primary objective of the LEOPARD study (Liquid biopsy in Ewing sarcoma and osteosarcoma as a prognostic and response diagnostic) was to determine whether patients with detectable pre-treatment ctDNA have an inferior event-free survival (EFS) compared to patients with undetectable ctDNA. Methods: The LEOPARD study is a prospective multicenter ctDNA study for patients with bone sarcomas. Patients enrolled through 12 primary study sites, or provided samples after enrolling on the Children’s Oncology Group Project EveryChild (ABTR18B1-Q). Eligible patients were 1-50 years of age at enrollment, had unresected, high-grade, localized, non-pelvic osteosarcoma and were to receive standard chemotherapy (primary centers only). We utilized a validated ctDNA assay, ultra-low pass whole genome sequencing (ULP-WGS), for ctDNA quantification based on tumor aneuploidy (limit of detection 3%). We compared EFS according to baseline ctDNA burden using two pre-specified cut points (detectable/undetectable [≥3%] and ~median [≥5%]. We planned 113 patients for 80% power to detect a difference in 2-year EFS of ~20% or greater for patients with detectable baseline ctDNA (2-year EFS: 68%) vs undetectable ctDNA (2-year EFS: 87%; one-sided log-rank test; ⍺ =0.05). Results: From 10/1/17 to 3/3/23, 138 patients with osteosarcoma met eligibility and enrolled (67 - primary study centers; 71 - ABTR18B1-Q). 133 patients had an evaluable pre-treatment ctDNA measurement. Median age was 14.2 years (range: 4.2-30.3) and 50% of patients were male. At diagnosis, 63% had detectable ctDNA [median: 5.3% (range: 0-43.1)]. Age, sex, race, ethnicity, and tumor size were not associated with a difference in ctDNA burden. Baseline detectable ctDNA burden (≥3%) was associated with an increased risk of EFS-event (relapse/progression, second malignant neoplasm, death) compared to undetectable ctDNA (2-year EFS: 56% [95% CI 45-68%] vs. 88% [95% CI 78-98%]; P< 0.0001; Table). A similar pattern was seen using a cut point of ≥5% (53% [95% CI 41-67%] vs. 83% [95% CI 74-94%], P< 0.0001). Conclusions: These findings validate prior data associating baseline ctDNA detection with inferior EFS in patients with localized osteosarcoma and identify the first prospectively validated molecular biomarker in this disease. Baseline ctDNA burden is now positioned for implementation into upcoming therapeutic trials of risk-stratified therapy in localized osteosarcoma. [Table: see text]
Predictive gene signature for trabectedin efficacy in advanced soft‐tissue sarcoma: A Spanish group for research in sarcoma (GEIS) study.
Authors: Moura David Silva , Cordero Varela Juan A. , Alvarez Ramiro , Agra Pujol Carolina , Izquierdo Francisco , Ramos Rafael , Ortega Luis , Martin-Davila Francisco , Hernandez Leon Nieves , Romagosa Cleofe , Vaz-Salgado Maria Ángeles , Lavernia Javier , Bague Silvia , Mayodormo-Aranda Empar , Mondaza-Hernandez Jose Lucinio , Renshaw-Calderon Marta , Hindi Nadia , Valverde Morales Claudia , Martínez-Trufero Javier , Martin Broto Javier 
Published: June 2024

11543 Background: Predictive biomarkers of trabectedin represent a clinical unmet need to support the rational selection of this drug in the advanced soft‐tissue sarcomas (STS) setting. A few potential predictive biomarkers of trabectedin had been described in previous studies, including ERCC1, BRCA1, and HMGA1, among others; however, they are based mostly on the analysis of single selected molecular factors. We presented here a predictive transcriptomic-based signature for trabectedin efficacy in STS. Methods: A total of 140 patients with advanced STS (at diagnosis or at any time from then on), with paraffin tumor block available, with at least 2 lines of treatment in advanced disease (one of them trabectedin) were included in this study. Gene expression was evaluated by direct transcriptomics, using HTG EdgeSeq Oncology Biomarkers Panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Raw counts were normalized to transcripts per million (TPM). Univariate Cox regression analysis was performed to find genes significantly associated with PFS and only those genes with significantly different curves were further retained (P < 0.05). These remaining genes were used as input to build a gene expression signature, using a multivariate Cox regression applying a Lasso penalty. Risk scores were calculated by multiplying the expression of every gene with its corresponding Cox regression coefficient. Results: A series of 140 patients was studied, with a median age of 51, 54% males, and a median follow-up from diagnostics of 45 months. The most frequent subtypes were L-sarcomas (54%). A twenty-nine-gene predictive signature of trabectedin efficacy was built for advanced STS treatment. This signature included 13 and 16 genes associated with resistance or sensitivity to trabectedin, respectively. Genes associated with low efficacy of trabectedin included HMGA1, NES, FANCA, and FANCB, among others, whereas the high expression of genes such as NTRK2 or CDKN2Awere associated with higher activity of trabectedin. Patients in the high‐risk gene signature group showed a significantly worse PFS compared with patients in the low‐risk group: [2.0 months (95% CI 1.7-2.2) vs. 8.2 months (95% CI 5.1-11.3), p<0.001]. Conclusions: Our study identified a new 29-gene-based signature that significantly predicts trabectedin efficacy in STS patients. Prospective validation of this predictive gene signature is warranted.
Anlotinib versus placebo as adjuvant therapy for completely resected high-grade soft tissue sarcomas: Interim results of a phase 2, double-blinded, randomized controlled trial.
Authors: Wang Chun-Meng , Hu Xianglin , Yang Ling-ge , Xu Yu , Huang Wen-Ding , Zhang Jian-rong , Sun Zheng-Wang , Chen Mo , Zheng Bi-qiang , Zhang Sheng-jian , Yu Lin , Fujiwara Tomohiro , Chen Yong , Sun Yang-bai , Houdek Matthew T. , Yan Wangjun 
Published: June 2024

11562 Background: High-grade soft tissue sarcomas (STS) pose a therapeutic challenge due to the high risk of recurrence, even following complete resection. Anlotinib is a multi-targeted tyrosine kinase inhibitor blocking angiogenesis pathways of VEGFR, FGFR, and PDGFR. Given a promising efficacy for treating patients with unresectable advanced STS in previous trials, we evaluated the role of anlotinib as adjuvant therapy for completely resected high-grade STS. Methods: In a single-center, double-blinded, randomized, controlled trial, eligible patients were those adults who had not received adjuvant chemotherapy regimens after complete resection of high-grade STS. Patients were randomly assigned in a 1:1 ratio to receive either oral 12 mg anlotinib or placebo once daily on days 1-14 every 3 weeks as a cycle, with up to six cycles until disease recurrence, unmanageable toxicity or death. The primary endpoints included 1-year, 2-year disease-free survival (DFS). Results: Between June 2019 and November 2023, 88 patients were randomly assigned to receive anlotinib (n=44) or placebo (n=44). With a median follow-up of 25.99 months at data accrual cutoff on Jan 15, 2024, the 1-year and 2-year DFS rates were 88% and 77% in the anlotinib group, compared to 64% and 58% in the placebo group. Compared to patients in the placebo group, patients in the anlotinib group had a reduced risk of disease recurrence (HR 0.47 [95% CI 0.22~1.00, P= 0.0445]). The median DFS was not reached. Based on tumor histology, the greatest improvement in DFS with anlotinib versus placebo was observed in patients with myxofibrosarcoma (1-year DFS rate: 82% versus 61%; 2-year DFS rate: 64% versus 43%, HR 0.54 [95% CI 0.17~1.65], P= 0.2698) and undifferentiated pleomorphic sarcoma (1-year DFS rate: 86% versus 67%; 2-year DFS rate: 78% versus 67%, HR 0.58 [95% CI 0.12~2.87], P= 0.4971). Thirty-eight patients experienced adverse events (AEs; 34 with grade 1~2, 4 with grade 3): 28 patients (64%) in the anlotinib group versus 10 patients (23%) in the placebo group ( P<0.001). Three patients discontinued anlotinib, including two for proteinuria/hematuresis (2/44, 5%) and one for secondary poor surgical wound healing (1/44, 2%). Conclusions: Current results suggest anlotinib could lower disease recurrence risk in patients with completely resected high-grade STS, with an acceptable toxicity profile. Clinical trial information: NCT03951571 . [Table: see text]
Intimal sarcomas (ISarc) of the cardiac chambers (CC) of the heart and great vessels (GV): A comprehensive genomic profiling (CGP) study.
Authors: Bou Zerdan Maroun , Pavlick Dean , Ross Jeffrey S. , Graziano Stephen L. , Basnet Alina 
Published: June 2024

11575 Background: ISarc of the CC and GV are extremely rare primary tumors of the cardiac chambers (CC), aortic root (AO) and pulmonary artery (PA). These tumors are rarely resectable and are associated with rapid progression and poor clinical outcome. We queried whether CGP could uncover new routes to targeted therapies for this aggressive form of malignancy. Methods: 27 cases of ISarc were centrally reviewed and required direct association with the intimal surfaces of the CC and GV with supporting routine histologic features and immunohistochemical staining patterns. DNA and RNA extracted from the ISarc cases were both sequenced using a hybrid-capture based CGP to study all classes of genomic alterations (GA) and determine MSI status, TMB level, HRD score, genomic ancestry, cosmic trinucleotide signature (Signature) and germline status. PD-L1 expression was measured by IHC (Dako 22C3 and TPS scoring). Results: The 27 ISarc cases included 15 CC and 12 GV (11 pulmonary artery ISarc and 1 aortic root Isarc). There were 24 (88.9%) histologic grade 3 and 3 (11.1%) grade 2 tumors. Median ages for all ISarc ranged from 45 to 46 years and were similar in both groups. The CC ISarc pts tended to be female when compared with the GV pts (73% vs 50%; P=.26). GA potentially impacting targeted therapy selection in clinical trials for rare tumors included amplifications of MDM2 in 66.7% of CC ISarc and 50% of GV ISarc, PDGFRA in 53.3% CC and 41.7% of GV; homozygous deletions in CDKN2A in 26.7% in CC vs 66.7% of GV was near significant (p=0.055) and significantly more frequent point mutations in PIK3CAin CC at 20% vs 0% in GV (p=.007) and ERBB3 in 13.3% of CV and 8.3% of GV which was not significant. EUR ancestry was present in slightly more than 50% of ISarc cases and similar in both sub-groups. Median TMB was similar and ranged from 4.3 to 4.7 mutations/Mb with 1 (6.7%) CC ISarc having a TMB of > 10 mut/Mb. 1/5 (20%) tested ISarc cases stained for low level PD-L1 expression. Conclusions: CGP of ISarc cases reveals that these tumors do feature a modest number of GA potentially associated with benefit for targeted therapies but low and absent biomarkers predictive of immunotherapy benefit. Further study of ISarc in a setting of rare tumor clinical trials appears warranted. [Table: see text]
Technology-enhanced palliative care for patients with advanced cancer undergoing phase I therapies: A pilot randomized clinical trial (RCT).
Authors: Hui David , Subbiah Ishwaria M. , Hong David S. , Ellefson Jennifer , Becerra Josue , De la Cruz Vera J , Urbauer Diana L. , Shete Sanjay , Bruera Eduardo 
Published: June 2024

12017 Background: Outpatient palliative care (PC) has been found to improve quality of life (QOL). It is not known if more frequent symptom monitoring and PC nursing contacts between clinic visits would offer additional benefits. We conducted a pilot RCT to examine the effect of a specialist PC referral with and without technology-enhancement (TEC) on symptoms in patients undergoing Phase I cancer therapies. Methods: This single-center parallel group RCT enrolled adult patients with advanced solid tumors prior to starting Phase I therapies and at least 1 Edmonton Symptom Assessment Scale (ESAS) symptom ≥4/10 and ESAS Global Distress Score (GDS) ≥20/90. Patients were randomized to PC alone or PC + TEC in a 1:1 ratio. Over the 12 w period, the PC group had in person or virtual outpatient visits with a PC physician, nurse, and as needed psychotherapist every 4 weeks; the PC + TEC group also received weekly symptom monitoring with ESAS electronically and weekly nursing phone call. The primary outcome was within-group change of GDS from baseline to 2 w; secondary outcomes included change in GDS over 4, 8, and 12 w, and change in QOL (FACIT-Sp) over 2, 4, 8 and 12 w. We estimated that a sample size of 50 patients per group would provide 90% power to detect a within-group GDS difference of 6 units with a 2-sided α of 2.5% and 20% attrition. Results: Between 12/15/2020 and 12/21/2022, 115 patients were enrolled and 101 were randomized (PC + TEC n = 57, PC n = 44). By 2 w, PC + TEC showed a significant within-group improvement in GDS (mean change -5 [95% CI -8.9, -1.2]; P= 0.01) but not PC alone (Table). PC+TEC group also had a significant improvement in GDS at 8 w and 12 w and in FACIT-SP at 2 w, 8 w and 12 w. PC alone group had a significant within-group improvement in GDS at 4 w and 12 w but no significant differences in QOL were detected. This study was not powered for between group comparison; however, FACIT-SP at 12 w was significantly higher in PC+TEC vs. PC alone (Table; mean difference 13.9; P= 0.02). Conclusions: Higher intensity of PC with closer monitoring showed within-group improvement in symptoms and QOL, while PC alone had some symptom reduction but no QOL improvement. Further studies are needed to confirm the QOL benefit of PC + TEC over PC alone. Clinical trial information: NCT04989556 . [Table: see text]
The effect of sodium glucose cotransporter-2 inhibitors on mortality and cardiovascular outcomes of patients with prostate cancer receiving luteinizing hormone releasing hormone agonists.
Authors: Tang Zhiting , Chiang Cho Han , Chang Yu-Cheng , See Xin Ya , Wang Qian , Chi Kuan-Yu , Chiang Cho Hung 
Published: June 2024

12025 Background: Luteinizing hormone releasing hormone agonists (LHRHa) are the standard of care treatment for prostate cancer but associated with an increased risk of cardiotoxicity. Recent studies suggest that sodium glucose cotransporter-2 inhibitors (SGLT2i), a class of antidiabetic drugs, reduce the risk of cardiovascular events compared to other glucose-lowering agents. We aim to investigate the potential cardioprotective effect of SGLT2i in prostate cancer patients with T2DM undergoing LHRHa therapy. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with prostate cancer and T2DM who were treated with LHRHa for prostate cancer and received either SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) for diabetes. The primary outcomes were all-cause mortality, incident hypertension, and incident major cardiovascular adverse events (MACE), which was defined as a composite of heart failure, myocardial infarction, and atrial fibrillation/flutter within 5 years of LHRHa initiation. Results: We matched 932 patients treated with an SGLT2i to patients treated with a DPP4i. The median age was 73 years for both cohorts. A total of 110 and 275 patients died in the SGLT2i and DPP4i cohorts, respectively. In Cox proportional hazard analyses, SGLT2i was associated with a reduction in the risk of all-cause mortality (Hazard ratio (HR), 0.65 [95% CI, 0.52 to 0.81]), hypertension (HR, 0.40 [95% CI: 0.22-0.70]) and major adverse cardiovascular events (HR, 0.70 [95% CI, 0.50 to 0.97]) compared to DPP4i. Similarly, SGLT2i was associated with a statistically significant reduction in heart failure and myocardial infarction. There appeared to be a tendency toward a lower risk of atrial fibrillation/flutter. Conclusions: The use of SGLT2i was associated with a lower risk of mortality, hypertension, and cardiovascular events in patients with prostate cancer and T2DM undergoing LHRHa therapy. [Table: see text]
Fasting mimicking diet reduces anti-OX40/anti PD-L1 and anti-PD-1/anti-CTLA-4 cardiovascular side effects in preclinical melanoma models.
Authors: Quagliariello Vincenzo , Cortellino Salvatore , Delfanti Gloria , Di Mauro Annabella , Tatangelo Fabiana , Spagnolo Vanessa , Visco Euplio , Casorati Giulia , Chiodoni Claudia , Della Bona Paolo , Blazevits Olga , Ascierto Paolo Antonio , Maurea Nicola , Longo Valter 
Published: June 2024

12029 Background: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation as cancer therapeutics with the potential to increase survival. However, ICIs-induced side effects ranging from autoimmune endocrine disorders to mucositis and to a rare but clinically significant cardiotoxicity with high rate of mortality represent important limitations. Cardiovascular complications in ICIs-treated patients includes myocarditis, vasculitis, arrhythmia, fibrosis and heart failure. Moreover, both the limited efficacy in a large portion of patients and the acquisition of resistance represent additional limitations for ICIs, underlining the need for new immunotherapy strategies. Fasting mimicking diets (FMDs) applied for several days periodically are emerging as highly promising enhancers of a wide variety of cancer therapies including immunotherapy. Here, a preclinical study in melanoma-bearing mice treated with two combinatorial ICIs therapies (anti-OX-40/PDL-1 or antiCTLA-4/anti-PD-1) during a standard or FMD was performed. Methods: Melanoma or lung cancer-bearing mice ( C57BL/6J female mice, 6–8 weeks old) were treated with two combinatorial ICIs therapies (anti-OX-40/PDL-1 or antiCTLA-4/anti-PD-1) during a standard diet or FMD for 21 days. Tumors were measured every 3–4 days using a digital caliper. Mice were monitored for tumor growth and survival. Mice were killed when tumor volume reached 1.5 cm3. Flow cytometry analysis of tumor-infiltrating lymphocytes and apoptosis, collagen quantification in myocardial tissues, quantification of CD3+ and CD8+ cells in myocardial tissues, of plasma and myocardial cytokines, and several pro-inflammatory biomarkers were performed through selective ELISA methods and western blotting analysis. Results: FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity. Conclusions: This study sets the stage for clinical trials aimed at assessing the ability of FMD to increase the efficacy of immunotherapy while reducing its side effects. These results also indicate that the anti-inflammatory and protective effects of FMD cycles in combination with ICI could affect other organs and systems.
Effect of anti CTLA-4 and PD-1 monoclonal antibodies on systemic SDF-1 and galectin-3 levels through NLRP3 and MyD-88 pathways in preclinical models.
Authors: Iovine Martina , Quagliariello Vincenzo , Passariello Margherita , Bruzzese Francesca , Palma Giuseppe , Luciano Antonio , Maurea Carlo , Berretta Massimiliano , Giacobbe Ilaria , Barbato Matteo , Giordano Vienna , Arianna Raffaele , Izzo Francesca , Ascierto Paolo Antonio , Bisceglia Irma , Canale Maria Laura , De Lorenzo Claudia , Maurea Nicola 
Published: June 2024

12032 Background: Immune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed. Methods: Firstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and ten days (T10), ejection fraction, radial/longitudinal strain were calculated by using echocardiography. Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β and IL-6 were analyzed before, during and after ICIs therapy. Results: Radial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs. Conclusions: Short therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3 in preclinical models. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.