bluuebunny/crossref_metadata_2025_split huggingface dataset:
2.5D transient electromagnetic inversion based on the unstructured quadrilateral finite-element method and a geologic statistics-driven Bayesian framework
Authors: Dai Qianwei , Wu Yun , Yue Jianhua 
Published: June 2024

The uncertainty of subsurface resistivity can be determined using Bayesian inversion during electromagnetic exploration. However, the extensive sampling necessary for Bayesian inversion may result in high computational costs and prevent its application in complex large-scale 2D and 3D electromagnetic inversions. For the first attempt, we implement a 2.5D (i.e., 3D source with 2D geologic model) Bayesian inversion to analyze ground transient electromagnetics (TEM) and make some adaptations and improvements. To be specific, we use geostatistical-based random modeling as a prior constraint strategy and incorporate additional prior information through model mapping to improve its performance in adapting to complex terrains. To perform preinversion of prior parameters, we use a spatially constrained transdimensional Bayesian inversion approach, extracting priors for the formal inversion from the posterior of the preinversion. This not only reduces computation time but also lessens the formal Bayesian inversion’s reliance on prior selection. Furthermore, to obtain more realistic uncertainty assessments, we design a likelihood suited to the noise characteristics of TEM. The extensive statistical analysis of posterior results provides richer insights than previous methods, showing Bayesian inversion’s superiority in uncertainty reliability and resistivity recovery effectiveness over deterministic inversion and continuous 1D Bayesian inversion. Comparative studies with multiple simulated models and applications to complex terrain goaf areas validate the effectiveness and superiority of our algorithm.
Outcomes and immune response after peptide vaccination targeting human cytomegalovirus antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma.
Authors: Thompson Eric , Ashley David M. , Ayasoufi Kathy , Norberg Pamela , Archer Gerald E. , Buckley Evan , HERNDON JAMES E , Walter Ashley , Archambault Bridget , Flahiff Charlene , Jaggers Denise , Gorski Laura , Reap Elizabeth A. , Schroeder Kristin , Desjardins Annick , Johnson Margaret O , Peters Katherine B. , Khasraw Mustafa , Sampson John H. , Landi Daniel B 
Published: June 2024

2039 Background: The human cytomegalovirus (CMV) antigen pp65 is ubiquitously expressed in high-grade glioma (HGG) and medulloblastoma but not in adjacent brain. The primary objective of this first-in-human phase I trial (NCT03299309) was to assess the safety and feasibility of a novel peptide vaccine targeting pp65 (PEP-CMV) in children/young adults with recurrent medulloblastoma and HGG. Methods: The vaccine is comprised of a synthetic long peptide of 26 amino acids and is administered as an emulsion in Montanide ISA 51. Patients receive a single 5-day course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning to promote dendritic cell migration, then PEP-CMV administered intradermally in the groin every two weeks for 3 doses, then monthly. Results: Forty-two patients were enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=21), anaplastic oligodendroglioma (n=3), anaplastic astrocytoma (n=11), and malignant glioma NOS (n=5). The median time from initial diagnosis to treatment was 24 months (range 4-35) and the median number of prior chemotherapy regimens was 4 (range 0-15). The mean age was 23.2 ± 9.3 years. 55% of patients were male. The median KPS was 80. Of the 38 patients who received PEP-CMV, the maximum grade adverse event (AE) possibly, probably, or definitely related to PEP-CMV was as follows: 17 (45%) had Grade 1 adverse events (AE), 16 (42%) had Grade 2 AEs, 2 (5%) had Grade 3 AEs (encephalopathy and pyramidal tract syndrome), and one (3%) had a Grade 4 AE (cerebral edema). One patient developed symptoms and had elevated inflammatory cytokines consistent with cytokine release syndrome (Grade 2). The median progression-free survival was 2.5 months (95% CI:2.2,3.2) and median overall survival was 6.4 months (95% CI:3.4,7.9). The 12-month OS was 26.6% (95% CI:14,41.1%). Of the 22 patients with evaluable immune monitoring data, T cell reactivity on IFNγ pp65 ELISpot was increased after PEP-CMV delivery (median spot pretreatment vs. prior to vaccine #4: 1 vs 30, P=0.004, Table). Lower percentage of pretreatment regulatory T cells and higher percentage of terminally differentiated effector T cells at vaccine #4 were associated with longer subsequent survival. Conclusions: PEP-CMV is well-tolerated and elicits an antigen-specific immune response in heavily pretreated, multiply recurrent patients with a 12-month OS of 26.6%. A multi-institutional Phase II trial (NCT05096481) of PEP-CMV is opening imminently. Clinical trial information: NCT03299309 . [Table: see text]
Phase I clinical trial of 64Cu-ATSM for malignant brain tumors.
Authors: Kurihara Hiroaki , Narita Yoshitaka , Ito Kimiteru , Sato Hidemitsu , Miyakita Yasuji , Takahashi Masamichi , Yanagisawa Shunsuke , Okita Natsuko Tsuda , Sadachi Ryo , Tateishi Kensuke , Yoshii Yukie , Waki Atsuo , Hashimoto Hiroki , Suzuki Hisashi , Zhang Ming-Rong , Kawamura Kazunori , Honda Natsuki , Yoshimoto Mitsuyoshi , Matsumoto Hiroki 
Published: June 2024

2052 Background: Malignant brain tumors such as glioblastoma have poor prognosis. Current standard therapies such as surgery, radiotherapy, and chemotherapy were frequently insufficient. Hypoxic tissue microenvironments induced by rapid cellular growth within tumor lesions lead to treatment resistance. Methods: Eligible patients had a histological diagnosis of grade III/IV glioma, primary central nervous system malignant lymphoma (PCNSL), or grade II/III malignant meningioma based on the most recent pathological diagnosis prior to enrollment, or metastatic brain tumor based on clinical course or imaging. Diacetyl-bis( N4-methylthiosemicarbazone) radiolabeled with Cu-64 (64Cu-ATSM) was synthesized as described elsewhere. 64Cu-ATSM was administered intravenously once a week for 4 weeks. Adverse events were assessed using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The trial had a traditional single arm open-label 3 + 3 design with four 64Cu-ATSM dose cohorts: 30, 60, 99, and 150 MBq/kg. The primary objective was to assess dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) of 64Cu-ATSM. Overall survival (OS), progression-free survival (PFS), pharmacokinetics, and 64Cu-ATSM effective radiation dose were evaluated as secondary endpoints. Results: In total, 20 patients were registered at National Cancer Center Hospital or Kanagawa Cancer Center. Eighteen patients who received 64Cu-ATSM were included in the primary analysis. None of the 3 patients at 30 MBq/kg, 1 of 6 patients at 60 MBq/kg, and 1 of 6 patients at 99 MBq/kg developed DLT (grade 3 lymphocytopenia). Two of 3 patients at 150 MBq/kg developed DLT (grade 4 lymphocytopenia). Therefore, additional patient recruitment was terminated. The MTD was considered to be 99 MBq/kg. No serious adverse events caused by 64Cu-ATSM administration were not reported. Median OS was 29.4 months and 1-year OS was 76.6%. Median PFS was 3.8 months and 1-year PFS was 19.0%. 64Cu-ATSM was rapidly distributed to body organs after intravenous administration and subsequently disappeared gradually. The liver (0.23 mSv/MBq) received relatively high doses, with an estimated effective dose of 0.037 mSv/MBq. Conclusions: Intravenous administration of 64Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options. Clinical trial information: jRCT2091220362 .
Cost-effectiveness of dabrafenib plus trametinib in BRAFV600E-mutant pediatric low-grade glioma: A microsimulation study.
Authors: Gascon Bryan , Yang Alan , Gauvreau Cindy , Bennett Julie , Nobre Liana , Tabori Uri , Hawkins Cynthia , Pechlivanoglou Petros , Denburg Avram 
Published: June 2024

2055 Background: BRAFV600E mutations, detected in 15-20% of pediatric low-grade gliomas (PLGGs), have emerged as a key therapeutic target for patients with unresectable, progressive, or recurrent PLGG. In a recent phase II clinical trial (NCT02684058), dabrafenib, a selective inhibitor targeting BRAFV600E, plus trametinib outperformed standard chemotherapy as first-line therapy, demonstrating significantly longer progression-free survival and improved safety in BRAFV600E-mutant PLGG. The aim of this study was to estimate the cost-effectiveness of dabrafenib+trametinib (Dab-Tram) versus standard chemotherapy as first-line therapy for patients with BRAFV600E-mutant PLGG. Methods: We constructed a microsimulation model, simulating a cohort of 10,000 patients with BRAFV600E PLGG. We populated the model using progression-free and overall survival estimates derived from the NCT02684058 trial, a hospital-based PLGG registry and treatment- and PLGG-related adverse events from published literature. The simulated cohort was assigned to either targeted therapy or chemotherapy as first-line therapy. Key parameters included treatment cost, dosage, inpatient and outpatient costs, and health-related quality of life. We assumed a lifetime duration of targeted therapy, a healthcare system perspective, lifetime horizon, and discount rate of 1.5%. Outcomes included life years, quality-adjusted life years (QALYs), lifetime costs (2022 CAD), and incremental cost-effectiveness ratios (ICERs).Sensitivity analysis included the use of alternative data sources, including those derived from independent assessment of NCT02684058 trial outcomes and real-world data from The Hospital for Sick Children (SickKids) in Toronto, Canada. Results: Modeled life years with Dab-Tram and chemotherapy were 34.91 and 32.68 years, respectively. Dab-Tram was associated with a 1.77 QALY increase at an incremental cost of $2,701,409 compared to standard chemotherapy. The resulting ICER was $1,526,265 per QALY gained. At a willingness-to-pay (WTP) threshold of $150,000 per QALY, a price reduction of approximately 80% is required to render it cost-effective. Scenario analysis varying effectiveness of targeted therapy using independent assessment of NCT02684058 trial outcomes and real-world data from SickKids demonstrated comparable clinical benefits and ICERs. Results were sensitive to changes in survival distributions. Conclusions: While clinical outcomes using Dab-Tram as first line therapy for BRAFV600E PLGG are promising, our model-based analysis demonstrates that at the present price, Dab-Tram is not cost-effective, and would require a considerable price reduction to enable equitable access and affordability. This work also provides an exemplar for economic evaluation of precision therapies based on emergent trial and real-world data for rare diseases.
Claudin18.2-targeted chimeric antigen receptor T cell-therapy for patients with gastrointestinal cancers: Final results of CT041-CG4006 phase 1 trial.
Authors: QI Changsong , Liu Chang , Gong Jifang , Li Jian , Liu Dan , Wang Xicheng , Zhang Panpan , Qin Yanru , Zhang Miao , Peng Zhi , Zhou Jun , Zhang Xiaotian , Peng Xiaohui , Wang Yumeng , Zhang Zijing , Yuan Daijing , Liu Zhen , Baffa Raffaele , Li Zonghai , Shen Lin 
Published: June 2024

2501 Background: Autologous anti-claudin18.2 (CLDN18.2) CAR T cell, satricabtagene autoleucel (satri-cel)/CT041, was investigated in gastrointestinal cancers in clinical trials. The interim results of CT041-CG4006 trial (NCT03874897) were published in June 2022 [1]. Herein, we present the final results of this trial. Methods: This single-arm, open-label, phase 1 trial evaluated the safety and efficacy of CT041 in patients (pts) with CLDN18.2-positive advanced gastrointestinal (GI) cancers. The trial consisted of a dose-escalation (250×106, 375×106, 500×106 or 1000×106cells) using modified ‘3+3’ design and dose expansion of CT041 in 4 cohorts (Cohort 1: CT041 in pretreated pts with advanced GI cancers, Cohort 2: CT041 plus anti-PD-1 therapy in pretreated pts with advanced GI cancers, Cohort 3: CT041 sequential treatment following first-line therapy in gastric cancer (GC) and Cohort 4: CT041 in pts with prior failure to anti-CLDN18.2 antibody). The primary endpoint was safety; secondary endpoints were efficacy using RECIST v1.1, pharmacokinetics, and immunogenicity. Results: From 26 March 2019 to 26 January 2024, a total of 98 pts received CT041 infusion, including GC (n=73), pancreatic cancer (n=10), biliary tract cancer (n=4), intestinal cancer (n=8) and other tumors (n=3). A total of 89 pts were dosed with 250×106, 6 pts with 375×106, and 3 pts with 500×106 cells, with a median follow-up of 29.7 (range: 1.2, 35.5) months. 250×106 was selected for the dose-expansion stage based on the dose-escalation results. The most commonly reported treatment-emergent adverse events of grade 3 or higher were hematologic toxicity related to lymphodepletion. No dose-limiting toxicities, treatment-related deaths, or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of pts, all classified as grade 1-2. Gastric mucosal injuries were identified in 8 (8.2%) pts, including 7 cases of grade 1-2 and 1 case of grade 3 gastritis erosive which recovered. For all pts (N=98), the ORR and DCR reached 37.8% and 75.5%, respectively. The median PFS and median OS were 4.4 (95% CI: 4.0, 6.0) months and 8.4 (95% CI: 7.0, 10.0) months for all pts. Among efficacy evaluable GC pts who received CT041 monotherapy, the ORR and DCR in those with measurable disease (n=47) reached 57.4% and 83.0%, respectively, and the median PFS and median OS in all efficacy evaluable GC pts (n=55) were 5.8 (95% CI: 4.2, 8.4) months and 9.7 (95% CI: 7.1, 14.4) months, respectively. Conclusions: Satri-cel/CT041 demonstrated a promising safety profile and highly encouraging efficacy in heavily pretreated patients with CLDN18.2-positive advanced GI cancers. Clinical trial information: NCT03874897 .
BGB-A317-212: A multicenter, open-label, phase II study to evaluate the efficacy and safety of tislelizumab in combination with lenvatinib in patients with selected solid tumors.
Authors: Liu Yufei , He Zhisong , Zhang Mingjun , Jiang Shusuan , Zhang Dahong , Feng Miao , Qu Shenhong , Ju Wutong , Wang Ke , Abdrashitov Ramil , Feng Jifeng 
Published: June 2024

2610 Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has demonstrated promising efficacy in several advanced solid tumors. However, some patients (pts) do not respond or develop resistance to tislelizumab monotherapy. Lenvatinib, a receptor tyrosine kinase inhibitor targeting VEGFR 1-3, FGFR 1-4, PDGFR alpha, KIT, and RET, has shown a potential synergistic effect with anti-PD-1 therapy. Here, we report the primary results of a phase II study evaluating the combination of tislelizumab plus lenvatinib in pts with solid tumors (NCT05014828). Methods: Pts with histologically/cytologically confirmed selected solid tumors, naïve to lenvatinib and anti-programmed death-ligand 1 (PD-L1)/PD-1 therapies were enrolled. Part 1 (safety run-in) determined the recommended phase II dose (RP2D) of lenvatinib in combination with tislelizumab 400 mg IV every 6 weeks. In Part 2 (expansion), pts received lenvatinib at the RP2D from Part 1 (20 mg orally/day) plus tislelizumab per the Part 1 regimen until disease progression, withdrawal, or death. The primary endpoints were safety and RP2D determination (Part 1) and overall response rate (ORR; Part 2). Results: At data cutoff (Oct 20, 2023; median follow-up 12.1 months [mo; renal cell carcinoma, RCC]; 10.8 mo [head and neck squamous cell carcinoma, HNSCC]; 14.8 mo [gastric cancer, GC], and 22.0 mo [non-small cell lung cancer, NSCLC]), 58 pts were treated in Part 2 (RCC, n=23; HNSCC, n=27; GC, n=3; NSCLC, n=5), 6 of whom were also included in Part 1. The ORR was 66.7% in pts with RCC, 33.3% (HNSCC), 33.3% (GC), and 20.0% (NSCLC). Median duration of response (mDoR) was 18.5 mo and 9.6 mo in pts with NSCLC and HNSCC, respectively; not estimable (NE) for RCC and GC (Table). No new safety signals were identified; grade ≥3 treatment-related adverse events were reported in 78.3%, 59.3%, 33.3% and 60.0%, of pts with RCC, HNSCC, GC, and NSCLC, respectively (Table). Conclusions: Tislelizumab plus lenvatinib had a manageable safety profile and showed preliminary antitumor activity in pts with selected tumor types. Longer follow-up is needed to further investigate the potential of this combination to benefit pts with advanced solid tumors. Clinical trial information: NCT05014828 .[Table: see text]
Phase 2 trial of brentuximab vedotin (BV) with pembrolizumab (pembro) in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or cutaneous melanoma (SGN35-033): Overall survival.
Authors: Zakharia Yousef , Lee Sylvia , Jotte Robert M. , Gillespie-Twardy Amanda Lynn , Mehmi Inderjit , Chandra Sunandana , Hamid Omid , Watson Graham Thomas , Ward Patrick J. , Chaney Marya F. , Lu Hailing , Berndt Jason , Rathi Kapil , Gupta Anumeha (Anu) , Cowey Charles Lance 
Published: June 2024

2617 Background: BV, a CD30 directed antibody-drug conjugate, may selectively deplete a subset of regulatory T-cells (Tregs) that express CD30 and re-sensitize tumors to anti-PD-1 therapy. This ongoing, multi-cohort, multicenter, open-label trial evaluating the efficacy and safety of BV+pembro in patients (pts) with anti-PD-1 refractory solid tumors previously reported an ORR (8-22%), DCR (67-80%), and CD8+T cell infiltration in on-treatment biopsies of responders (Lee, SITC 2023). Here we report OS and biomarker analyses. Methods: Pts with primary refractory (progression without response or SD for < 6 months) or secondary refractory (progression after response for ≥3 months or SD for ≥6 months) NSCLC or melanoma who progressed on anti-PD-1 therapy were included. Pts received BV (1.8 mg/kg) and pembro (200 mg) every 21 days. The primary endpoint was confirmed ORR. Exploratory endpoints included OS and biomarker analyses of blood and tumor samples. Results: 55 pts with NSCLC and 58 pts with melanoma were dosed (86% white, 63% male; 57% ≥ age 65 yrs). Pts received 3 median prior lines of therapy (as previously reported). Investigator-assessed response was measured according to RECIST v1.1. At a median follow up of 17.2 months, median OS (mOS) was 13.9 months (NSCLC) and 12.9 months (melanoma) (Table 1). The estimated probability of survival (Kaplan-Meier) at 12 months was 54.0% (95% CI 43.69, 63.22) for the study population. Immune mediated AEs were reported in 25% of pts, Grade ≥3 TEAEs in 56%, TESAEs in 42%, and TE peripheral neuropathy (SMQ) in 48% of pts. 17% of pts discontinued treatment due to TEAEs. No new safety signals were identified and no deaths due to treatment-related AEs were reported. Paired tumor biopsies from 19 pts showed increased CD8+T cell infiltration in 11 pts. Conclusions: These data support the immunomodulatory capacity of BV with pembro. This combination shows encouraging OS data in pts with solid tumors who have progressed on anti-PD-1 therapy. The safety profile is comparable to previously reported data. The study remains ongoing. Clinical trial information: NCT04609566 . [Table: see text]
Clinical impact of molecular profiling in the national prospective cohort Solving Unknown Primary Cancer (SUPER) study.
Authors: Sivakumaran Tharani , White Matthew , Prall Owen , Mitchell Catherine , Dijkstra Christine , Rebello Richard , Xu Huiling , Vissers Joseph , Grimmond Sean , Wong Hui-Li , DeFazio Anna , Gao Bo , Singh Madhu Sudan , Collins Ian M. , Steer Christopher B. , Warren Mark Andrew , Karanth Narayan Vaderahobali , Bowtell David , Tothill Richard W , Mileshkin Linda R. 
Published: June 2024

3056 Background: Cancer of unknown primary (CUP) is a common cause of cancer death, with a median survival < 12 months. SUPER is a prospective cohort study designed to create a national information and biobank of patients (pts) with no confirmed primary site following diagnostic work-up. We aimed to determine the impact of tumour molecular profiling on treatment decisions. Methods: 449 pts were recruited (2013-2021) over 3 phases from 12 Australian sites. Clinical information collected over 12 months included: demographics, treatments, investigations and clinico-pathological characteristics. Molecular tests were centrally performed and included comprehensive panel (CCP) sequencing and gene-expression tissue of origin (TOO) assays in Phase 1&2 and CCP and whole genome sequencing (WGS) in Phase 3. The number of genes reported on increased over the 3 phases. Molecular results were discussed in a molecular tumour board. Clinicians completed clinical management questionnaires before and after receiving molecular results. A combined retrospective evaluation of therapeutic actionability was applied to all DNA sequencing data using the TOPOGRAPH database. Results: Median age 63 years [19-86], with 81% ECOG 0-1 and 87% classified as unfavourable CUP subtype. Reporting timelines and rates of successful sequencing improved over time (Table). Clinically actionable genomic abnormalities were detected in 95/331 (29%) pts. Moderate or high match results on TOO assay were consistent with a suspected or later confirmed TOO as reported by clinicians in 81/195 (42%) pts in phase 1 + 2. Germline pathogenic mutations were detected in 34/331 (10%) pts. Molecular tests confirmed clinician’s treatment (started while awaiting results) was consistent with the most likely TOO in 170/331 (51%) pts. Clinicians reported that molecular tests resulted in a change in management in 11/118 pts (9%) in phase 1 and 40/213 (19%) pts in phases 2+3, with 17/51 (33%) pts changed treatment based on potential TOO determination. 11/51 (22%) pts could access treatment via standard pathways given a more specific tumour-type diagnosis and 15/51 (29%) pts were potentially eligible for clinical trials; however, only 7 pts were well enough for referral. Conclusions: The clinical impact of molecular testing in CUP improved over time as testing became more sophisticated and turnaround times improved. Clinicians suspected TOO pre-profiling was consistent with molecular results in half of the pts. Routine access to novel therapies in CUP remains a challenge. [Table: see text]