bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.
Authors: Wang Huafeng , Wei Xudong , Liang Yang , Jiang Qian , He Wenjuan , Li Qiubai , Weng Jianyu , Chen Suning , Chang Chunkang , Ma Hongbing , Xu Yajing , He Qun , Chen Zi , Liu Lihui , Men Lichuang , Cong Danhua , Zhang Zhang , Yang Dajun , Zhai Yifan , Jin Jie 
Published: June 2024

6541 Background: Investigational agent lisaftoclax (Lisa) was shown in preclinical findings to synergistically induce apoptosis in acute myeloid leukemia (AML). Here, we present follow up safety and efficacy data from a phase 1b/2 study evaluating Lisa + azacitidine (AZA) in adults with AML. Methods: Elderly (≥ 75 years)/unfit treatment-naïve (TN) and relapsed or refractory (R/R) AML (≥ 18 years) patients (pts) were enrolled. Lisa (400/600/800 mg) was administered orally once daily in 28-day cycles (a daily ramp up schedule was used for Lisa to prevent tumor lysis syndrome, TLS) combined with AZA (75 mg/m2/day on D1-7). Results: As of January 25, 2024, 76 AML pts were enrolled (R/R [n = 37]; elderly/unfit TN [n = 39]). The median (range) age was 66 (20-81) years and 61.8% of pts were male. All pts treated with Lisa + AZA reported TEAEs, with 89.5% Grade 3/4 AEs; and 43.4% SAEs. Common TEAEs (≥ 30%) included neutropenia (60.5%), thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%), pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of pts were neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported, and the 30-/60-day mortality rates were 1.3% and 3.9%, respectively. In pts with R/R AML treated with Lisa + AZA, the overall response ([ORR] = CR + CRi + morphologic leukemia-free state [MLFS] + PR) and composite complete remission (CRc = CR + CRi) rates were 72.7% and 45.5%, respectively. In the 600 mg cohort (n = 30), ORR and CRc were 76.7% and 50.0%; the median (range) duration of treatment (mDoT), 3.8 (0.8‒15.4) month (mo); median time to CRc (mTTCRc), 2.5 (95% CI, 1.5-6.1) mo; median PFS was 10.2 (95% CI, 6.5-NR) mo; and median OS was 14.7 (95% CI, 7.8-NR) mo. Among 39 pts with TN AML treated with Lisa + AZA, ORR and CRc were 64.1% and 51.3%, respectively (Table). In the 600 mg cohort (n = 29), mDoT was 3.3 (1.0- 9.9) mo; mTTCRc was 1.9 (95% CI, 1.2-3.3) mo; median PFS was not reached (3.5, NR). 600 mg of Lisa + AZA was established as the recommended phase 2 dose. Conclusions: Our data support an emerging role for this new BCL-2 inhibitor Lisa combined with AZA for the treatment of elderly/unfit TN and R/R AML pts, especially with low early mortality and promising mPFS. A phase 3, randomized, double-blind clinical study is in progress to determine whether Lisa + AZA improves OS in elderly/unfit pts with AML. *HW, XW, and YL are co-first authors. Clinical trial information: NCT04501120 . [Table: see text]
Improved overall survival in acute myeloid leukemia over the last 15 years.
Authors: Dhakal Prajwal , Loeffler Bradley T. , Ravindra Aditya , Acharya Luna , Pyakuryal Avantika , Bhatt Vijaya Raj 
Published: June 2024

6543 Background: Overall survival (OS) for acute myeloid leukemia (AML) has remained dismal over the past decades. In the last five years, 11 drugs have been approved for newly diagnosed and relapsed/refractory AML. We, therefore, hypothesized that OS has increased significantly in recent years. Methods: We identified 78,092 pts diagnosed with AML between 2004 and 2019 from the National Cancer Database and divided them into 2 cohorts based on year of diagnosis, 2004-2010 and 2011-2019. The Kaplan-Meier method was used to estimate OS probabilities. Cox regression was used to evaluate the association of patient and disease characteristics with OS and differences in these associations between the two cohorts. Results: Sixty-one percent of patients were ≥60 years old, 46% were female, 85% were white, and 90% had Charlson comorbidity index of 0-1. Forty-five percent were diagnosed in 2004-2010, and the rest were diagnosed in 2011-2019. Chemotherapy use increased over the years, with 81% of patients receiving chemotherapy in 2019 compared to 73% in 2004. Similarly, 12.2% of patients in 2012 received hematopoietic cell transplant (HCT) compared to 6.5% in 2004. One-year, 3-year, and 5-year OS for patients diagnosed in 2011-2019 were 48%, 31%, and 28% compared to 42%, 25%, and 22%, respectively, for patients diagnosed in 2004-2010. On multivariable analysis, OS differed significantly over the years based on race, AML subtype, receipt of chemotherapy, and HCT use. OS for white people was better compared to black in 2004-2010 but similar in 2011-2019. Both white and black people had worse OS compared to other race types in 2004-2010 and 2011-2019. Acute promyelocytic leukemia had the best OS compared to core-binding factor, therapy-related, and other AML types; OS improved the most in acute promyelocytic leukemia and core-binding factor AML over the years. Compared to 2004-2010, OS increased significantly in 2011- 2019 with the receipt of chemotherapy and HCT. Older age, male sex, lower income, no insurance, higher Charlson comorbidity index, and lower educational attainment were associated with worse OS with no significant change in recent years. Conclusions: In one of the largest studies, we identified improved OS in patients with AML in recent years. Improvement in OS is likely multifactorial, including recent drug approvals, increased use of chemotherapy and HCT, and better supportive care. Despite a meaningful improvement in OS, only one out of four patients with AML were alive after five years, highlighting a continued need for further drug development and the importance of HCT.
Mutation patterns and prognostic implications in acute myeloid leukemia with chromosomal 7 deletions.
Authors: Kugler Eitan , Dasdemir Enes , Wang Bofei , Bataller Alex , Dinardo Courtney Denton , Daver Naval Guastad , Yilmaz Musa , Short Nicholas James , Kadia Tapan M. , Sasaki Koji , Bazinet Alexandre , Pierce Sherry , Reville Patrick Kevin , Ravandi-Kashani Farhad , Abbas Hussein 
Published: June 2024

6547 Background: Chromosomal 7 deletions (del7/7q) are the most common adverse cytogenetic event in acute myeloid leukemia and are associated with high rate of relapse. We analyzed gene mutation profiles in del7/7q AML patients who relapsed after initial remission to identify molecular patterns associated with clinical outcomes. Methods: Out of 351 newly diagnosed AML patients with del7/7q, 115 (32%) achieved complete remission after first-line treatment between 2012-2023. Of the 115 patients, 77 (67%) patients relapsed during the study follow-up. Kaplan-Meier and Cox regression were used to analyze survival outcomes. Next-generation sequencing was performed on a targeted panel of 81 genes for 59 patients who relapsed on bone marrow samples at diagnosis and relapse for paired analysis. Results: The median age of the 115 patients at diagnosis was 74 (41-93). Thirty-four patients (30%) received intensive treatment. With 30.8-month median follow-up, the median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months, p=0.005) or complex karyotype (12.4 vs. 8.6 months, p=0.03). The median duration of response for the 77 patients who relapsed was 5 months (2-7). Allo-HSCT significantly improved median OS (not reached vs. 8.5 months, P=6e-06), and was identified as the key variable impacting survival in multivariate analysis. TP53 was the most commonly mutated gene at diagnosis (67%) and relapse (71%). Mutations in CBLC and KDM6A were cleared after induction therapy, while BCOR and BCORL1 were commonly acquired at relapse (Table). At diagnosis, a lower co-mutation burden was observed in TP53 mutant patients as compared with wild type (average 1.84 vs. 3.65 respectively, p=0.0001). Patients with mutated TP53 and coexisting mutations in GATA2, NF1, BCORL1, or RUNX1 at diagnosis had shorter relapse free survival (RFS, 2 vs. 5 months, p=0.01) and OS (7.2 vs. 10.4 months, p=0.01) compared to patients with solely mutated TP53 (HR 2.2; 95% CI 1.2-4; P = 0.004). Allo-HSCT significantly improved the OS in patients with mutated TP53 (13 vs. 8 months, p=0.01). Conclusions: Mutated TP53 clones persist from diagnosis to relapse in patients with del7/7q AML. In patients with mutated TP53, co-occurring mutations in GATA2, NF1, BCORL1or RUNX1 at diagnosis were linked to a shorter RFS and indicate a particularly high-risk subgroup that require proceeding to allo-HSCT in CR1 without delay. [Table: see text]
Depletion of histone H3K27 demethylase exerts anti-tumor activity as a monotherapy and in combination therapy with ceralasertib in non-small cell lung carcinoma.
Authors: Lee Pony Yu-Ling , Lin Kun-Yuan , Chang Chao-Di , Cheng Shan-Yun , Hung Ya-Wen , Yang Chih-Chieh , Chang Yu-Hsien , Shen Chien-Chang , Yeh Lin-Wen , Aberin Marvin Angelo Esteban , Wang Shu-Ping 
Published: June 2024

e20035 Background: Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) represents 85% of lung cancers and is the most common type with poor prognosis. The lysine-specific demethylase UTX (gene name KDM6A) demethylates H3K27me2/3 at genes and enhancers and have been shown to support oncogenic transcription factors. We hypothesize that UTX is a highly pleiotropic factor in tumorigenesis and may plays a critical role in controlling DNA replication-associated gene activation as well as in replication stress-related DNA damage repair. Methods: To evaluate the role of UTX in tumorigenesis, shRNA-mediated UTX knockdown was employed in NCI-H1975 cells followed by cell cycle and cell proliferation assays. In the UTX-knocked down NCI-H1975 cells, target genes involved in DNA replication and DNA damage repair were discovered by RNA sequencing and further validated with RT-qPCR. Effects of UTX depletion on DNA replication and radiation-induced DNA repair were analyzed by immunofluorescence. Effects of UTX depletion on cell cycle arrest and the ATR–CHK1 checkpoint signaling pathway were analyzed by flow cytometry and immunoblotting. In vivo response to UTX inhibition monotherapy (UTX knockdown) and combination therapy of UTX knockdown with ceralasertib, a selective ATR kinase inhibitor, was evaluated in dox-inducible UTX knockdown NCI-H1975 xenografts. Results: Induction of UTX knockdown significantly reduced the NCI-H1975 tumor volume compared to the control group, showing anti-tumor activity. Furthermore, loss of UTX induced hyperactivation of ATR–CHK1 checkpoint signaling pathway, suggesting the UTX-depleted tumor cells attempt to alleviate replication stress to escape from apoptosis. To inhibit the UTX-depletion induced ATR–CHK1 pathway, ceralasertib (formerly AZD6738), an oral potent selective inhibitor of ATR, was combined with UTX-knockdown for in vitro and in vivo evaluation. Consistent with in vitro cell-based assay, combination therapy of ceralasertib with UTX depletion showed enhanced tumor growth inhibition and regression in the NCI-H1975 xenograft model. Conclusions: Our findings provide new insights into a pro-oncogenic role of UTX in supporting tumor maintenance via engaging DNA replication and repair pathway. Depletion of UTX alone may serve as a new therapeutic target in non-small cell lung carcinoma; and further combination with ceralasertib enhances the anti-tumor activity of UTX knockdown by inhibiting the ATR–CHK1 checkpoint signaling pathway.
Predicting spread through air space and immune status in lung adenocarcinoma by CT-based deep learning model.
Authors: Zhou HaiYu , Li Qiaxuan , Cai Linghan , Xie Daipeng , Yao Lintong , Lei Yu , Cai Canjia , Zhang Qi 
Published: June 2024

e20043 Background: Tumor spread through air space (STAS) is a novel histologic pattern of invasion related to high recurrence and poor prognosis. Meanwhile, there is a potential relationship between STAS status and the tumor immune microenvironment. The aim of this study was to predict STAS status in lung adenocarcinoma (LUAD) using a CT-based 3D-CNN deep learning model and explore the tumor immune microenvironment in the GSE58661 cohort. Methods: We retrospectively collected data from 368 patients with lung adenocarcinoma and STAS status from Guangdong Province General Hospital between 2021 and 2023. We performed propensity score matching (PSM) based on gender, year, BMI, and smoking status to obtain a cohort of 368 patients without STAS status. A 3D-Resnet-Resnetearning model was developed to identify the STAS status of lung adenocarcinoma, and the performance of the models was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity. Meanwhile, bule RNA sequencing and baseline CT of LUAD from 41 patients in the GSE58661 cohort and the TCIA dataset were used to investigate the potential biological mechanism in the patients with STAS status. Results: We included 584 and 152 patients in the training and testing sets, respectively. The 3D-Resnet algorithm was used in the 3D patch with voxel sizes of 128*128*128, 96*96*96, and 64*64*64 to construct the DL-STAS model. With the training set's AUC of 0.899, the results showed that the model achieved an AUC, sensitivity, specificity, and accuracy of 0.884, 0.831, 0.838, and 0.835 in the testing cohort, respectively. According to our model, we divided the patients in GSE58661 into STAS and non-STAS. By identifying and analyzing the differentially expressed genes between the STAS and non-STAS groups, we found that several immune-related pathways, such as the T cell receptor signaling pathway, the PD-1/PD-L1 expression pathway, the natural killer cell-mediated cytotoxicity pathway, and the macrophage activation pathway, were enriched in the group with STAS status. Conclusions: The DL-STAS model we developed has great potential for accurately predicting STAS status in lung adenocarcinoma. In the meanwhile, the prognosis of patients with STAS status may be impacted by their particular tumor immune microenvironment.
Association of tissue microbiota with cancer stages in lung adenocarcinoma.
Authors: Su Yanfang , Li Shiyu , Sang Die , Zhang Yurong 
Published: June 2024

e20061 Background: There has been a lack of comprehensive investigation into changes in the tissue microbial environment at various stages of lung adenocarcinoma (LUAD). This study aims to identify and analyze microbial markers that show significant differences at different stages of LUAD and to assess their impact on the tumor microenvironment. Methods: Microbiome data, gene expression, and clinical information from LUAD patient tissues were retrieved by reanalyzing the sample sequencing data from the Cancer Genome Atlas (TCGA) database, as conducted by Rob Knight’s group. The samples, categorized into early (pathological stage I) and late (stages II-IV) following the initial diagnosis, were subjected to comparative analyses. Firstly, microbial alpha diversity metrics, such as the Shannon index, were computed for each sample. Subsequently, Principal Coordinate Analysis (PCoA) and the Wilcoxon rank sum test were employed to assess differences in microbial communities between the two groups. Furthermore, the study delved into the associations between microbes and host gene expressions using Spearman rank correlation to construct a heterogeneous network encompassing microbial interaction networks at the genus level, microbe-gene interaction network, and gene co-expression network. Various network features, including the clustering coefficient, were examined. Finally, diverse machine learning algorithms were employed to develop a diagnostic model for cancer stage based on microbial and gene expression data. Results: A total of 491 samples, including 267 in the early group and 224 in the late group, were matched with microbial data, mRNA expression, and clinical information. Our findings revealed distinct differences in the microbiome of patients with LUAD at various stages, particularly in the tissues of advanced patients, where in the co-abundance network exhibited a significantly higher level of complexity. Furthermore, we identified five bacterial biomarkers (Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, Loktanella, and Serratia) that were associated with the LUAD stage. Notably, Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, and Serratia were significantly overexpressed in advanced patients. Utilizing the random forest model, we determined that microbial markers possess predictive capabilities for the stage of lung adenocarcinoma and can compensate for deficiencies in other omics data for determining tumor stage. Integration of the mRNA and intratumor microbe biomarkers yielded a prediction area under the Receiver Operating Characteristic curve of 0.70. Conclusions: Our study unveiled the microbial profile of LUAD patients, elucidating the intrinsic pathogenic mechanisms linking the microbiome and the disease. Additionally, we developed a multi-omics model for determining the tumor stage of LUAD.
A phase II trial of monalizumab in combination with durvalumab (MEDI4736) plus platinum-based chemotherapy for first-line treatment of extensive stage small cell lung cancer (MOZART): Hoosier Cancer Research Network LUN21-530 study.
Authors: Mamdani Hirva , Kim Seongho , Gentzler Ryan D. , Shields Misty Dawn , Furqan Muhammad , Pizana Kristen , Abid Qura , Jalal Shadia Ibrahim 
Published: June 2024

TPS8129 Background: Chemoimmunotherapy consisting of platinum, etoposide, and PD-L1 inhibitor remains the standard of care first-line treatment for extensive stage small cell lung cancer (SCLC) yielding median overall survival (OS) of slightly over a year. NKG2A/CD94 is an immune checkpoint that is selectively expressed on natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. When engaging with its ligand, HLA-E, NKG2A transduces inhibitory signals that suppress immune-mediated cytotoxicity. Thus, NKG2A blockade enhances anti-tumor immunity by promoting both, NK and CD8+ T cell, effector functions. Monalizumab, a monoclonal antibody targeting NKG2A, enhances NK cell activity against tumor cells and rescues CD8+ T cell function in combination with PD-(L)1 axis blockade. Pre-clinical data have demonstrated that the absence of NK cells substantially enhances metastatic dissemination of SCLC tumor cells in vivo. NK cell function is modulated in response to cytotoxic chemotherapy, especially platinum. Post-chemotherapy NK cells display an induced expression of NKG2A compared with pre-chemotherapy patients and is associated with a reduced NK cell mediated anti-tumor activity. Hyperactivation of NK cell activity ameliorates SCLC metastases, an effect that is enhanced when combined with anti PD-(L)1 therapy. Altogether, these data suggest that addition of monalizumab to standard of care first-line treatment may be associated with improved efficacy in patients with SCLC. Methods: Patients with extensive-stage SCLC with ECOG performance status of 0-2 and adequate organ function are eligible for enrollment on this single-arm phase II study with an initial safety lead-in cohort. Patients may have received one prior cycle of platinum doublet with or without durvalumab and may have treated or untreated asymptomatic brain metastasis. Patients will receive platinum (cis or carbo), etoposide, durvalumab, and monalizumab every 3 weeks for 4 cycles followed by durvalumab and monalizumab every 4 weeks until disease progression or unacceptable toxicity. Primary endpoints include 1-year progression-free survival, safety, and tolerability. Secondary endpoints include objective response rate, 1-year overall survival, and intracranial progression-free survival. Exploratory objectives include analyzing association of treatment efficacy with minimal residual disease status, blood- and tissue-based genomic and transcriptomic signatures, tumor infiltrating immune cells, and peripheral blood NK cell and CD8+ T cell activity. Five of the planned 30 patients have been enrolled to date. Clinical trial information: NCT05903092 .
Dose and Time Effects of Renin–Angiotensin Inhibitors on Patients With Advanced Stages 4 to 5 of Diabetic Kidney Disease
Authors: Chen Yi-Chun , Tung Chien-Hsueh , Yu Ben-Hui 
Published: June 2024

Abstract

Context
Limited evidence exists regarding the cumulative dosing and duration impact of renin–angiotensin system inhibitors (RASis) on cardiorenal and mortality outcomes in patients with advanced stages (predominantly in stage 5 and a minority in stage 4) of diabetic kidney disease (DKD).

Objective
To retrospectively investigate whether there are dose- and time-dependent relationships between RASis and cardiorenal and mortality outcomes in this population.

Methods
Using Taiwan's national health insurance data in 2000-2017, we analyzed 2196 RASi users and 2196 propensity-matched nonusers among 8738 patients living with diabetes and newly diagnosed with advanced chronic kidney disease (23% stage 4, 77% stage 5). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% CI.

Results
RASi use was significantly associated with reduced risks of all-cause mortality (aHR, 0.53; 95% CI 0.47-0.60) and cardiovascular mortality (0.68; 0.56-0.83) with the degree of benefit depending on therapeutic dosage and duration, despite a nonsignificant increase in acute kidney injury risk (1.16; 0.98-1.38) and a significant increase in hyperkalemia risk (1.45; 1.19-1.77). Significant differences in proteinuria risk (1.32; 1.21-1.43) were observed, while there were no significant differences in end-stage renal disease risk (1.01; 0.88-1.15) and no dose– or time–response relationships for either end-stage renal disease or proteinuria risks. Sensitivity analyses confirmed cardiovascular and survival benefits, even in patients with stage 5 DKD.

Conclusion
This real-world study suggests that RASi use in advanced stages 4 to 5 DKD may provide dose- and time-dependent cardioprotection and improved survival, without excess renal harms.
Evaluating the content and face validity of Arabic-translated Patient Measures of Safety survey PMOS-30
Authors: Alaska Yasser A. , Alqahtani Nawaf M. , Al Zahrani Amani K. , Alshahri Rawan , Malyani Rana Z. , Alkutbe Rabab B. 
Published: June 2024

Background
The importance of patient perception of patient safety has been proven as an active role in promoting safety and predicting harm. Patients play a vital role in the healthcare sector and the impact of patient perception of patient safety has been repetitively proven in the literature to be for its effectiveness in predicting harm and promoting safety. Nonetheless, there is limited knowledge about the specific insights patients can provide concerning safety within Arab countries. Therefore, improving and strengthening active patient participation by including patients’ perceptions of safety could offer novel contributions to the realm of patient safety.

Objective
This study aims to evaluate the validity of the Arabic version of the PMOS-30.

Method
The forward-backward translation procedure was used to translate and validate the PMOS-30. Mix methods were used to assess the validity of the translated version. The expert raters evaluated the content validity and interviews were conducted with in-patients to assess the face validity. Test-retest approach was conducted to pilot the final Arabic version.

Results
Data of face validity from 13 participants for the first test and 5 participants for the re-test was collected and showed an improvement in the clarity rate (71.50% and 94.66% respectively). With respect to the content validity of the final version, the CVI was 0.92, indicating excellent relevant results.

Conclusion
The final version of the revised was approved by the expert to be a valid tool to measure patient perceptions of patient safety in Arabic-speaking patients to be utilized on patient safety improvement initiatives.