bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of simvastatin on PD-L1 via ILF3 to enhance CD8+ T cell-mediated ferroptosis in gastric cancer cells.
Authors: Sun Danping , Yu Wenbin , Cui Xiaohan 
Published: July 2024

e16056 Background: Immunotherapy is vital in the comprehensive treatment of gastric cancer (GC). However, the prognosis of GC patients remains unfavorable, necessitating to exploration of novel therapeutic approaches and medications. Methods: PD-L1 expression was observed using small interfering RNA and plasmid to knock down and overexpress ILF3, respectively. The expression of ILF3, PD-L1, and ferroptosis marker molecules (SLC7A11 and GPX4) was detected upon simvastatin stimulation of gastric cancer cells co-cultured with activated CD8+ T cells. To assess the impact of ILF3 and simvastatin stimulation on the induction of ferroptosis in gastric cancer cells by CD8+ T cells, various assays including CCK8, MTT, ROS, Fe2+, MDA, GSH, and LPO were conducted. Cleavage under targets and Tagmentation (CUT&Tag) was employed to validate the mechanism of simvastatin by regulating ILF3 expression. Whole genome sequencing and KEGG analysis reveal that ILF3 regulates PD-L1 expression through the DEPTOR/mTOR signaling pathway. Results: Statin treatment decreased the serum levels of ILF3 and PD-L1. This study found that ILF3 was positively correlated with the expression of PD-L1, and the knockdown of ILF3 effectively inhibited the expression of PD-L1, thus enhancing the cytotoxicity of CD8+ T cells to gastric cancer cells. Meanwhile, simvastatin inhibited the expression of PD-L1 through ILF3, which enhanced the induction of ferroptosis in gastric cancer cells by CD8+ T cells. Further studies found that simvastatin inhibited ILF3 expression by decreasing the acetylation level at residue site H3K14 in ILF3, while ILF3 inhibited PD-L1 expression through the DEPTOR/mTOR pathway. Conclusions: Simvastatin further recruited CD8+ T cells to enhance anti-tumor immunity by inhibiting PD-L1 expression by ILF3 and induced GC cells to undergo ferroptosis to achieve synergistic immunotherapy. This study elucidated the new mechanism of statins to improve GC immunotherapeutic effect. It revealed a new theoretical basis for using statins in GC treatment to improve the prognosis of GC patients.
Induction immunotherapy-based regimens followed by palliative CCRT may lead to conversion surgery in selected patients and boost survival for stage IV ESCC.
Authors: Chen Jo-Pai , Lu Wei-Chen , Hsueh Fu-Jen , Chiang Keng-Man , Chen Hsing-wu , Peng Shang-Hsuan , Chang Chen-Han , Hong Ruey-Long 
Published: July 2024

e16059 Background: ESCC is still a health burden in Taiwan; besides, double cancers easily occur in Taiwan, like HypoCa & ESCC or OSCC and ESCC. ESCC is still an immunogenic cancer type. Nivolumab with chemotherapy or nivolumab with ipilimumab in CM648 study and pembrolizumab with chemotherapy in KN590 study have also won survival benefits compared with chemotherapy alone in frontline treatment for R/M ESCC, esp. for PDL1+ patients. In our previous study, EGFR TKI, such as afatinib, have multiple immuno-modulatory effects and may help to increase immunotherapy benefits in the 1st line(67% ORR) of CT-unfit advanced ESCC. Following KN590 or chemotherapy failure, good rescue efficacy(70% ORR) was also seen in subsequent afatinib with anti-PD1.(ASCO-GI2022). Methods: We try to analyze the treatment options and final survivals of 72 patients with stage IV ESCC from 2010 to 2019 in my institution from National Taiwan University Hospital, Yun-lin Branch. Results: See Table. Conclusions: In this 10-year experience in one institution, we suggested induction Immuno-chemotherapy, Bio-immunochemotherapy, & Bio-immunotherapy may lead to coversion chemoradiation, even to final surgery for stage IV ESCC with well systemic control in selected fit patients to boost further survival. Maintenance metronomic UFUR with anti-PD1 may also be beneficial. Afatinib with anti-PD1 could be a good option for (1)frontline treatment for double cancers or CT-unfit patients; (2)salvage treatment in later lines, even failing KN590 or CM648. [Table: see text]
The role of determining HER2neu status in patients with gastric cancer.
Authors: Kadyrbayeva Rabiga , Kaidarova Dilyara , Smagulova Kaldigul , Medetbekova Elmira , Turkpenova Innara , Dmitrenko Maria , Kaldarbekov Samat , Nurmukhambet Ayaulym 
Published: July 2024

e16067 Background: Over the past two decades, gastric cancer has continued to maintain a leading position in both incidence and mortality rates among all malignant neoplasms in the Republic of Kazakhstan. Recent data indicate that amplification or overexpression of the HER2 gene is detected in 7-34% of gastric cancer cases, significantly impacting treatment outcomes. Studying a specific group of patients with HER2 overexpression in gastric cancer is of great interest in clinical oncology. Research aim: To examine the long-term treatment outcomes in patients with gastric cancer depending on the status and level of HER-2 expression in real clinical practice. Methods: Analysis was conducted on 172 formalin-fixed paraffin-embedded samples of gastric adenocarcinoma and gastroesophageal junction carcinoma, subjected to immunohistochemical examination to determine HER2 protein expression. Patients' ages ranged from 18 to 85 years, with a mean age of 61.7 years; among them, 106 (61.6%) were male and 66 (38.4%) were female. Of the 172 patients, 64 (37.2%) had primary tumors located at the gastroesophageal junction, while 108 (62.8%) had tumors located in the body of the stomach. Based on differentiation grade, the majority were G3-100 (50%), G2-91 (45%), G1-9 (5%). HER2 testing was performed on the Ventana BenchMark Ultra platform using the HER2 (4B5) antibody. Results: HER2 overexpression was detected in 26 (15.1%) of the 172 patients. Patients with HER2 2+ non-amplified were 6 (3.5%), HER2 2+ amplified were 8 (4.6%), HER2 1+ was detected in 19 (11%) cases, and HER2 0 was found in 121 (80.9%) cases. Long-term results revealed statistically significant differences, notably the highest overall survival rate in patients with HER-2 overexpression compared to HER-2 low and absence of HER-2. The HER2 3 (+FISH/SISH) variant was significantly more prevalent in 84.6% compared to HER2 0 in 52%, and HER2 1 in 48%, p < 0.05. Comparison of Her2 status using the chi-square method in groups revealed probable differences concerning tumor localization, with a criterion value of 0.034; morphological form (criterion value = 5.83); and differentiation grade (criterion value = 10.05). Conclusions: These results underscore the importance of further HER2 research in gastric cancer and gastroesophageal junction carcinoma for the development of personalized therapeutic strategies.
Advanced signet ring cell type gastroesophageal cancers in Latin American patients age 40 and below: A summary of one tertiary care center's experience and a review of the literature.
Authors: Cannon Timothy Lewis , Randall Jamie , Swain Whitney Rose , Mani Haresh , Wadlow Raymond Couric , Huynh Jasmine , Winer Arthur 
Published: July 2024

e16069 Background: Gastric Cancer mortality rates in Latin American countries of Central and South America (LA) are among the highest in the world. After observing multiple cases of advanced gastric adenocarcinoma (GA) with signet ring cell differentiation in young immigrants from LA, we sought to understand the prevalence and demographics of young-onset gastric cancer at our institution. Methods: We used the Inova Fairfax Hospital cancer registry to perform a retrospective cohort study by identifying all patients ≤ 40 from 2013-2022 with 1) GA, and 2) all cancers, and comparing the percentage of LA patients in each group. We noted a trend towards high rates of GC in young immigrants of LA six years ago, and now provide an updated analysis. We then reviewed phenotypic characteristics of each tumor, including signet ring cell differentiation, Her-2/Neu overexpression, and H. Pylori status and the time interval between diagnosis and death. Results: From 2013-2022, 21/37 patients (56.8%) ≤ 40 with GA were from LA (Table 1), with the majority from El Salvador. 95% (20/21) of LA patients had tumors with signet ring cell morphology, 88% (14/16) of non-LA patients had tumors with signet ring cell morphology. In comparison, patients that self-identified as “Hispanic/Spanish” made up 8.1% of subjects ≤ 40 with all cancers during the same time period. Conclusions: At our tertiary care center, Stage IV signet ring cell gastric cancer is highly prevalent in young patients from Latin America. Further exploration of epidemiological risk factors is warranted. [Table: see text]
Characteristics, treatment, and outcomes of cutaneous mantle cell lymphoma: A decade-long study at MD Anderson Cancer Center.
Authors: Gaulin Charles , Zhang Jared R. , Wu Susan Y. , Jain Preetesh , Ok Chi , Yan Fangfang , Chen Wendy , Oriabure Onyeka , Dabaja Bouthaina Shbib , Gunther Jillian Rebecca , Fang Penny , Pinnix Chelsea Camille , Wang Michael 
Published: July 2024

e19037 Background: Mantle cell lymphoma (MCL) is a rare B cell neoplasm that accounts for 6% of all non-Hodgkin lymphomas and affects predominantly older Caucasian males. Cutaneous involvement is rare in MCL, but more commonly occurs in the advanced or terminal stages of the disease and lacks a standardized approach. Here we report our center’s experience with cutaneous MCL. Methods: We conducted a retrospective chart review of all MCL patients treated at the University of Texas MD Anderson Cancer Center from January 2013 to December 2023 and identified 20 MCL patients with cutaneous involvement. Demographic data, disease characteristics, imaging findings, therapies, and survival outcomes were collected. The study was performed in accordance with the guidelines of the institutional review board. Results: Among the 20 MCL patients with cutaneous involvement (Table), nearly all were Caucasian (n=19/20, 95%), and most were male (n=14/20, 70%). The median age at cutaneous MCL diagnosis was 63.5 years (range: 50-83). All patients had advanced stage disease. The median interval from MCL diagnosis to the emergence of cutaneous symptoms was 2.2 years (range 0-9.3). Most had relapsed/refractory disease (n=17/20, 85%). Most patients had blastoid (n=13/19) or pleomorphic (n=4/19) cytology with a Ki-67 proliferative index ≥50% (n=19/20, median 90%). Several patients had p53 expression (n=11/14) and/or TP53 aberrations (n=4/16). Immediate subsequent systemic therapy, most commonly immunochemotherapy (n=9/20), led to frequent responses (overall response rate: 61%). Most patients received low-dose radiotherapy (RT) for their cutaneous disease (n=19/20) achieving high rates of local control (n=16/18). Of those who are alive and in complete response (n=3) at data cutoff, 2 received chimeric antigen receptor (CAR) T cell therapy as their last MCL-directed treatment. The median survival time from MCL diagnosis to death was 6.83 years (95% confidence interval (CI):4.20-not estimable (NE)). The median survival time from the diagnosis of cutaneous involvement to death was 3.16 years (95%CI: 1.93-NE). The median follow-up duration from MCL diagnosis was 8.22 years. Conclusions: Cutaneous involvement in MCL is associated with aggressive disease biology and poor survival outcomes. Low-dose RT with concurrent immunochemotherapy should be considered the current standard therapeutic approach. CAR T cell therapy and/or bispecific T cell engagers may further improve outcomes in these high-risk patients. [Table: see text]
Real-world evaluation of treatment pattern, time to next treatment (TTNT), healthcare resource utilization (HCRU), and cost of care in follicular lymphoma (FL).
Authors: Gaballa Sameh R , Xue Mei , Chuang Po-Ya , Esselman Kaitlyn , Furnback Wesley , Yang Keri 
Published: July 2024

e19044 Background: FL often becomes relapsed or refractory (R/R) to treatment. This study aimed to analyze TTNT, HCRU, and cost of care in FL. Methods: A retrospective study was conducted using Optum Clinformatics Data Mart to identify patients ≥18 years with ≥1 diagnosis for FL initiating 1L, 2L, 3L, or 4L treatment from 1/2019 to 02/2023. Patients were required to be continuously enrolled for 30 days pre- and post-index date, defined as the date of treatment initiation. Patients were categorized into mutually exclusive cohorts based on treatment regimen. TTNT was measured for patients who had a subsequent treatment within the study period. Total cost of care included both plan- and patient-paid claims, adjusted for inflation (2023 USD). HCRU included outpatient visits and inpatient admissions. Costs and HCRU were reported per patient per month over the treatment duration. Results: There were 4,525 patients initiating 1L treatment and 1,053, 304, and 97 patients initiating 2L, 3L, and 4L treatment, respectively. Median follow-up was 487 days (1L), 430 days (2L), 357 days (3L), and 276 days (4L). The mean age at the index was similar across cohorts (range: 69.6 [1L] to 71.9 [4L]). Rituximab monotherapy (R-mono) was the most utilized treatment in 1L and 2L, followed by bendamustine + rituximab (BR) and R-CHOP (Table). Lenalidomide + rituximab (R2) was the most utilized regimen in 3L and 4L. Obinutuzumab monotherapy (O-mono) use increased by line of therapy. The median TTNT across all regimens decreased by line of therapy (Table). BR and bendamustine + obinutuzumab (BO) had longer TTNT in 1L, while BR and R2 had longer TTNT in 3L. Inpatient admissions and outpatient visits increased with the line of therapy. Mean (SD) outpatient visits were 5.3 (3.2) in 1L, 5.8 (3.7) in 2L, 6.3 (4.0) in 3L, and 6.1 (3.3) in 4L, while inpatient admissions ranged from 0.1 (0.3) in 1L to 0.3 (0.4) in 4L. The mean total cost of care ranged from $40,538-$74,466, increasing by line of therapy. The mean total cost of care was consistently lowest in R-mono ($31,704-$36,197), while CAR-T had the highest total cost ($501,493-$522,378). R-mono had the lowest while R-CHOP had the highest mean outpatient visits across lines of therapy. Conclusions: Real-world TTNT decreased while costs and HCRU increased with each subsequent line of treatment, indicating a high disease burden in FL patients, particularly for those with R/R FL.These findings suggest the need for better treatment options for patients with FL, especially in 3L and 4L. [Table: see text]
Comparison of zanubrutinib (zanu) and acalabrutinib (acala) in B-cell malignancies: An adverse event (AE)-based analysis.
Authors: Munir Tahla , Wang Yucai , Mohseninejad Leyla , Srivastava Tushar , Gupta Anurag , Gautam Raju , Challagulla Swetha , Xue Mei , Yang Keri , Williams Rhys , Levy Vincent , Zhou Shouhao 
Published: July 2024

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [Table: see text]
A phase 1/2 study of BDC-3042, a novel dectin-2 agonistic antibody, in patients with advanced cancers.
Authors: Salkeni Mohamad Adham , Vandross Andrae L. , Dumbrava Ecaterina Elena , Giordano Antonio , Chen Christopher , Kenkel Justin , Cai Danlin , Xu Lu , Alonso Michael N. , Ackerman Shelley , Yu Tai , Colburn Dawn E. , Perez Edith A. , Wilks Sharon 
Published: July 2024

TPS2695 Background: Tumor-associated macrophages (TAMs) are a major component of the immune infiltrate in most cancers and play a key role in establishing the immunosuppressive tumor microenvironment (TME) that enables tumor progression. However, TAMs are phenotypically plastic and have the potential to be reprogrammed into immunostimulatory cells that enhance innate and adaptive anti-tumor immunity. BDC-3042 is a novel agonistic antibody targeting an immune-activating receptor expressed on TAMs known as Dectin-2 ( CLEC6A) [1]. Dectin-2 is a C-type lectin receptor best known for its role in pathogen recognition and induction of protective immune responses against fungi and other microbes. We have previously demonstrated that Dectin-2 agonism stimulates pro-inflammatory cytokine secretion and antigen presentation by TAMs, resulting in robust CD8+ T cell-mediated anti-tumor immunity in syngeneic mouse models [2]. Elevated gene expression of Dectin-2 has been found in a wide range of solid tumor types compared to non-malignant tissues. Nonclinical studies with BDC-3042 have demonstrated its potential to reprogram TAMs and elicit anti-tumor activity as a novel immunotherapeutic approach for diverse human cancers [2]. A phase 1/2, first-in-human, dose-escalation and dose-expansion study of BDC-3042 as a single agent and in combination with a cemiplimab in subjects with advanced cancers has been initiated. Methods: This study is enrolling up to 185 patients with advanced cancers, including non-small cell lung cancer, melanoma, triple-negative breast cancer, renal cell carcinoma, colon cancer, head and neck cancer, and ovarian cancer. Primary objectives of the dose-escalation phase are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-3042 as a monotherapy (Part 1) and in combination with cemiplimab (Part 2). The dose-expansion phase will evaluate preliminary anti-tumor activity of BDC-3042 monotherapy (Part 3) and with cemiplimab (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. Exploratory analyses will also be conducted to assess BDC-3042’s ability to reprogram TAMs and identify biomarkers associated with BDC-3042 biological activity and with cemiplimab. This study is being conducted in the US and is currently recruiting patients. 1. Kenkel J, et al. Cancer Res. 2023. 2. Kenkel J, et al. J Immunother Cancer. 2021. Clinical trial information: NCT06052852 .
A phase 1/1b, first-in-human, multi-part study of DF6215, an engineered IL-2Rα-active agonist, to investigate the safety, tolerability, pharmacokinetics, and biological and clinical activity in patients with advanced solid tumors.
Authors: Carneiro Benedito A. , McKean Meredith , Vicier Cecile , Valerin Jennifer Brooke , Tarhini Ahmad A. , Ganju Vinod , Ruisi Mary M. , Kirby Patrick , Cuillerot Jean-Marie , Romano Emanuela 
Published: July 2024

TPS2704 Background: IL-2 is a pleiotropic cytokine that stimulates strong anti-tumor responses by promoting expansion and activation of cytotoxic tumor-infiltrating immune cells including CD8 + T cells and NK cells (1). Aldesleukin is an approved rhIL-2; however, it has clinical limitations due to short half-life, requirement for 5 days of hospitalization per cycle, and high toxicity [eg, cytokine-related toxicity, capillary leak syndrome (CLS)] that limits its use [aldesleukin USPI]. DF6215 is a modified monovalent human IL-2 that binds to the IL2R. Preclinically, DF6215 administration results in sustained and modulated IL-2 pharmacology, leading to protracted pharmacodynamic (PD) effects and enhanced anti-tumor activity without observation of CLS in murine and primate toxicology studies. In response to the limitations of previous IL-2 therapeutics, DF6215 was designed as an IL-2Rα-active agonist with increased IL-2Rβγ stimulation to improve the benefit-to-risk ratio of historic IL-2 drugs. An additional design element is a prolonged elimination half-life due to Fc fusion, allowing for less frequent dosing. Methods: This is a first-in-human, open-label, multipart, Phase 1/1b clinical trial to characterize the initial safety, tolerability, pharmacokinetics, and preliminary efficacy of DF6215 in patients with advanced solid tumors. The Phase 1 dose escalation (DE) starting dose is 10 ug/kg IV every 2 weeks (up to 42 subjects expected to be enrolled), and the Safety/PK/PD will be explored at doses already characterized as safe in dose escalation and potentially efficacious (max of 40 subjects). Phase 1b includes an efficacy expansion (EE) cohort in subjects with advanced melanoma who have received prior anti-PD-1 agents and, if the tumor harbors a BRAF-activating mutation, a BRAF inhibitor. Key inclusion criteria include ≥ 18 years of age; ECOG PS of 0 or 1; adequate organ function, and locally advanced or metastatic solid tumors for which standard therapy options have been exhausted; and availability of baseline tumor biopsy. Primary objectives include determination of the MTD of DF6215 in DE and demonstration of clinical activity of DF6215 in the EE. Secondary objectives include assessment of safety and tolerability, pharmacokinetics, and immunogenicity of DF6215. This study plans to enroll up to 102 subjects across ~30 global centers in the US, European, and the Asia/Pacific regions, and is currently open to enrollment. 1. Arenas-Ramirez N, et al. 2015. Trends Immunol. Clinical trial information: NCT06108479 .