bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-β1 in colitis treatment
Authors: Zhang Qixiang , Zeng Zhu , Wei Ning , Su Yueyan , Wang Jing , Ni Qi , Wang Yukai , Yang Jingwen , Liu Xiaoyan , Xu Huanke , Wang Guangji , Shan Yunlong , Zhou Fang 
Published: July 2024

Abstract
Background
Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects.

Methods
First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD.

Results
The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis.

Conclusions
MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.
An inertial self-adaptive algorithm for solving split feasibility problems and fixed point problems in the class of demicontractive mappings
Authors: Berinde Vasile 
Published: July 2024

AbstractWe propose a hybrid inertial self-adaptive algorithm for solving the split feasibility problem and fixed point problem in the class of demicontractive mappings. Our results are very general and extend several related results existing in the literature from the class of nonexpansive or quasi-nonexpansive mappings to the larger class of demicontractive mappings. Examples to illustrate numerically the effectiveness of the new analytical results are presented.
Circulating tumor cells and tumor DNA in patients with resectable colorectal liver metastases: The MIRACLE.
Authors: Wullaert Lissa , Jansen Maurice P. H. M. , Kraan Jaco , Beaufort Corine M. , Van Ngoc M. , Belt Eric J. Th. , Vermaas Maarten , Gobardhan Paul D. , Sleijfer Stefan , Verheul Henk M.W. , Wilting Saskia M , Grunhagen Dirk J. , Martens John W.M. , Verhoef Cornelis 
Published: July 2024

3011 Background: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need for prognostic markers to detect minimal residual disease after local treatment. The aim of this study was to determine the association between recurrence-free survival (RFS) and detection of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) before and after surgical treatment of resectable CRLM. Methods: The MIRACLE isa prospective, observational biomarker study in patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy, recruited between October 2015 and December 2021. The study was powered to detect at least a 20% difference in one-year recurrence rate between detectable and undetectable circulating tumor load after surgery. Blood samples were collected one day before surgery (T0) and three weeks (T3) after surgery. CTCs were enumerated using the FDA-approved CellSearch system. ctDNA before surgery was measured by next generation sequencing (NGS) using a targeted panel (Oncomine Colon cfDNA assay) and postoperatively by digital PCR (dPCR). Results: CTC enumeration resulted in positivity for 43 out of 192 patients (22%) at baseline and 14 out of 161 patients (9%) at T3. ctDNA was detected in 125 out of 191 patients (65%) at baseline, of which 25 (20%) still had detectable ctDNA at T3. Patients with postoperative undetectable CTC had a significantly improved RFS (1-year RFS: 15% vs. 51%, log-rank test p=0.009). Also, patients with postoperative undetectable ctDNA had a significantly improved RFS (1-year RFS: 20% vs. 54%, log-rank test p<0.001). In multivariable analysis, at baseline no association was found between RFS and CTCs (HR 1.01; p=0.97) or ctDNA (HR 1.29; p=0.29). In contrast, after surgery a significantly shorter RFS was observed in patients with detectable CTCs (HR 3.09; p=0.002) and ctDNA (HR 3.53; p<0.001). Postoperative ctDNA status was a stronger predictor of recurrence compared to known clinical risk factors. Conclusions: This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of detectable circulating tumor load after surgery on RFS. Postoperative ctDNA and CTC detection are a strong predictor for a shorter RFS after local treatment, as opposed to preoperative ctDNA or CTC detection. [Table: see text]
Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).
Authors: Biesdorf de Almeida Carla , Engelhardt Benjamin , Babel Heiko , Badillo Jesus D , Sharma Manish , Powderly John D. , Neagu Aristide Martha Raluca , Freise Kevin Jay , Mensing Sven , Parikh Apurvasena 
Published: July 2024

3030 Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p < 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p < 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .
(CDK) 4/6 inhibitors: An effective treatment for homologous recombination deficient (HRD) luminal breast cancers (BC)?
Authors: Gouvêa Lucas , Santos Elizabeth , Cesca Marcelle , Lopes Mario Machado , Soldi Nathalia , Primo Basilio De Souza Viviane , Braga Fabricio , Silva Eduardda B. , Ferreira Izabella , Bertoli Victor , Fernandes Thaissa , Carneiro Amanda , Chinelato Juliana Rosa , Novello Roberto 
Published: July 2024

e13100 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) still represents the best 1st-line choice for hormone receptor (HR) positive(+)/HER2 negative(-) metastatic breast cancer (MBC) patients (pts). Approximately 8% of pts with HR+ BC harbors germline BRCA mutation (g BRCAmt). The interaction between Cyclin/CDK pathway, endocrine receptor (ER) and Breast Cancer gene 1/2 (BRCA1/2) is complex and evidence reported so far, await confirmation in the context of future randomized clinical trials. So far, limited data exist about treatment effectiveness of CDK4/6i in homologous recombination deficiency (HRD) Luminal BC. A current frequent question in clinical practice is which additional adjuvant therapy to prioritize for luminal BRCA tumors (tu), considering the approval of both CDK4/6i andpoly ADP ribose polymerase (PARP) inhibitors in this scenario. Considering potential impacts of genetic instability in tu biology, such as potential loss of Rb protein related to Loss of Heterozygosity (LOH) of BRCA2 as a primary resistance mechanism in CDK4/6i, we sought to analyze the clinical results of that drug in tu with genetic instability. Methods: We retrospectively analyzed real-world outcomes of CDK4/6i performance in HR+/HER2- MBC treated in a single institution, with focus in clinical outcomes of HRD BC. germline HR genes status and somatic phosphatidylinositol 3-kinase (PIK3CA) status were also analyzed. Results: A total of 384 consecutive MBC pts treated with CDK4/6i were included in this study. The most used CDK4/6i was palbociclib (40,6%), followed by ribociclib (29,8%) and abemaciclib (29,2%). Considering the whole cohort PFSm 30months (95%IC 26-34) and OSm were 56 months (95%IC 52-60) No differences in PFS or OS was observed among the 3 CDK4/6i. Median age of the cohort was 60 years old. 38.5% were premenopause Pts and 59.9% were postmenopause. A total of 149 (39%) pts performed germline screening. Between 19 pts with gHR mt, 12 were BRCA1/2 mt (just one BRCA1). The other were: 2 PALB2, 2 CHEK2, 1 ATM, 1 RAD51D, 1 RAD51C mt. So far, no differences in PFS ou OS was observed in the presence of BRCA 1/2 or other gHR mt. Nevertheless, PIK3CA mt was tested in 142 pts, 51 were positives. That mt was a predictor of worse OS (55m; 95%IC 45-65) x 63m (95%IC 56-69), p 0,019. Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6i may be worse in pts with HRD tu due to potential differences in tu biology. Future exploration in larger samples of patients who have had biomarker testing is ongoing. Patients with Pik3CA mt treated with CDK4/6i presented worse clinical outcomes.
Real-world data of efficacy and safety of denosumab on patients with breast cancer with bone metastasis: Results from Chinese clinical experience.
Authors: Liang Xu , Zhang Ruyan , Zhu Anjie , Gui Xin-Yu , Li Huiping , Song Guohong 
Published: July 2024

e13103 Background: Bone is the most common metastasis site in advanced metastatic breast cancer disease. Denosumab is advocated by various guidelines with high-quality of evidence for the treatment of breast cancer patients with bone metastases (BM) to delay or reduce the occurrence of skeletal related events (SRE). Data for bone lesion repair after treatment on image is still needed in real world. This retrospective study aims to evaluate the efficacy of denosumab on breast cancer with BM by MD Anderson (MDA) criteria which is specific to BM and its safety in real world. Methods: Data of patients age ≥18 years diagnosed with advanced breast cancer with BM and treated with denosumab from June 1st 2020 to Dec 31st 2022 were retrospectively analyzed. The primary endpoint was the objective response rate (ORR) for bone lesions by MDA criteria in evaluable patients. Secondary endpoints include disease control rate (DCR) for bone lesions, risk of SRE occurrence and safety in total population. Subgroup analysis investigated the impact of the time of denosumab treatment initiation post-diagnosis of BM as well as the duration of treatment with denosumab on efficacy. Comparative analysis was performed using Chi-squared test and a p value of <0.05 was considered statistically significant. Results: Atotal of 185 patients were enrolled with median age of 52.45 (SD: 12.02) years. The median follow-up time was 25.2 months. 49 out of the 130 evaluable patients achieved partial response, resulting in an ORR of 37.69% (95% CI: 0.29-0.47), and a DCR of 90% (95% CI: 0.84-0.95). 16 out of 185 (8.65%) patients developed SRE after denosumab treatment with the median time to the first occurrence of SRE not reached. The ORR and DCR for bone lesions of starting denosumab after diagnosis of BM in ≤3 months vs. >3 months were 31.54% vs. 6.15% (p<0.001) and 68.46% vs. 21.54% (p<0.001), respectively. The ORR and DCR for bone lesions of the duration of denosumab treatment <6 months vs. ≥6 months were 4.62% vs. 33.08% (p<0.001) and 37.69% vs. 76.92% (p<0.001), respectively. Renal function impairment decreased from 33 patients before treatment to 8 patients post-treatment, while hypocalcemia increased from 1.62% to 11.35%. Osteonecrosis of the jaw occurred in one patient (1/185,0.54%) post-treatment. Conclusions: Denosumab was found to be effective and safe for breast cancer patients with BM in this large retrospective study. Early initiation and longer duration of denosumab treatment may generate better clinical outcomes for bone lesions by MDA criteria.
Safety profile of sacituzumab govitecan in patients with breast cancer: A systematic review and meta-analysis.
Authors: Dacoregio Maria Inez , Michelon Isabella , Castro Caio , Moraes Francisco Cezar A. , Ravani Lis Victoria , Rossato de Almeida Guilherme , Vilbert Maysa , Costa Ricardo L. 
Published: July 2024

e13106 Background: Sacituzumab govitecan (SG), a first-in-class TROP-2-directed antibody conjugated to a topoisomerase inhibitor, has shown antitumor activity across various breast cancer (BC) subtypes. Following SG approval for metastatic triple negative breast cancer (TNBC) and its broad use, understanding SG’ safety profile is crucial. Hence, we conducted a systematic review and meta-analysis to evaluate the safety and tolerability of SG in patients with BC. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases, and ASCO and ESMO websites for clinical trials assessing the safety of SG in BC patients. Outcomes of interest included treatment-related adverse events (TRAEs) of any grade, grade 3/4, adverse events (AEs) leading to death, and AEs leading to SG dose reduction or discontinuation. All analyses were performed in R software (v.4.2.2) using random effects models. Heterogeneity was assessed using I2 test. Results: A total of 1,325 patients from six studies – three randomized clinical trials (RCTs) and three non-RCTs – were included. Median age of population ranged from 47 to 56 years. Most had metastatic disease (86%, n=1187), and triple-negative BC (48.6%, n=670). Regarding therapies, 798 patients received SG and 527 had treatment of physician's choice (TPC). In the pooled analysis of 748 patients on SG, the overall risk of AEs was 100% (95% CI 99-100%). The estimated risk of the most common all grade AEs were neutropenia (66%), anemia (44%), nausea (56%), vomiting (30%), fatigue (46%), constipation (17%), diarrhea (45%), and alopecia (46%), as described (Table). The risk of grade 3/4 AEs among 748 patients on SG was 55% (95% CI 36-74%). Neutropenia was the most important grade ≥3 AE, with a estimated frequency of 47%; followed by anemia and diarrhea, with an incidence of at 9% and 7%, respectively. The incidence of all other grade 3/4 AEs (e.g. anemia, vomiting, leukopenia, fatigue, constipation, and diarrhea) was below 10%. Dose reduction and discontinuation were observed in 14.4% and 2.9% of patients, respectively. Toxicity-related deaths occurred in six patients (0.4%). In a comparative sensitivity analysis of RCTs only, SG had significantly higher toxicity than TCPs, all grade AEs (OR 12.30 95%CI 1.68-89.87, p=0.01), and grade >3 AEs (OR 1.69 95%CI 1.25-2.28, p=0.0006). Conclusions: In this systematic review and meta-analysis, SG was associated with a high incidence of AEs. Neutropenia is a notable and potentially serious adverse event. Toxicity associated with SG may be addressed through close monitoring and early management. [Table: see text]
Prognostic factors for patients with breast cancer brain metastasis after stereotactic radiotherapy.
Authors: Xiong Jie , Chen Qiuchi , Zhao Yanxia 
Published: July 2024

e13109 Background: Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Numerous prognostic factors are associated with survival for patients with BCBMs. Here we investigated the clinical factors associated with overall survival (OS) and distant intracranial control (DIC) after stereotactic radiotherapy (SRT) for BCBM. Methods: The records of BCBM patients treated with SRT were collected from electronic database in Cancer Center, Union Hospital, Tongji medical college, Huazhong University of Science and Technology Hospital. Based on the univariate and multivariate Cox regression analysis, the prognostic significance of available variables was assessed. The nomogram was created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index, and the clinical benefits were evaluated through clinical decision curve analysis (DCA). Results: 101 BCBM patients receiving SRT were analyzed in this study, and 5 patients were excluded with other primary malignancies or missing data. Median observation time was 15.0 months, and median OS was 22.0 months. OS rate was 71.5% in 1 year, 45.8% in 2 years, and 32.8% in 3 years. DIC was 49.8% in 1 year, 26.6% in 2 years, and 18.3% in 3 years. Multivariable analysis identified prognostic factors for OS including number of the brain metastasis, molecular subtypes type, brain metastasis as the first metastasis site, Karnofsky performance status (KPS), and receiving systemic therapy after SRT. KPS<80, triple-negative subtype, the existence of extracranial metastases, the existence of lung metastases were associated with decreased DIC. Selected by the Akaike information criterion (AIC), the nomogram model contains age, KPS, histological subtype, number of brain metastases, brain metastasis as first metastasis site, PTV size, liver metastases, albumin and neutrophils. The calibration curve for probability of survival showed high consistencies between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.823, and the bias-corrected C-index generated by bootstrap validation with 1,000 resamples was 0.772, which was statistically higher than the C-index values of the other systems: Recursive partitioning analysis (RPA) (0.627), Graded prognostic assessment (GPA) (0.637), Breast-specific Graded Prognostic Assessment (breast-GPA) (0.699). BCBM patients receiving SRT were divided into four risk groups: I group (risk score < 150), II group (150≤risk score< 220), III group (220≤risk score<290) and IV group (risk score≥290). The Kaplan‐Meier OS curves showed great discrimination among the four risk groups. Conclusions: The proposed nomogram resulted in a more-accurate prognostic prediction for BCBM patients receiving SRT.
Investigating the outcome of vascular emboli in patients with breast cancer.
Authors: Hassan Abdelilah Tafenzi , Choulli Farah , Essadi Ismail , Belbaraka Rhizlane 
Published: July 2024

e13116 Background: Vascular emboli (VE) represent a critical event in breast cancer pathophysiology. Despite their clinical relevance, their relative impact on breast cancer outcomes remains underexplored. In this study, we delve into comparing the survival outcomes and recurrence rates of patients with and without VE in patients with breast cancer (BC) and adjust for other patient-related variables. Methods: This study was designed based on a retrospective cohort of pathologically confirmed de novo, local, or metastatic recurrence BC female patients diagnosed between 2020 and 2022 and aged > 18 years. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the effect of vascular emboli on survival and recurrence while controlling other reviewed demographic, clinic, pathologic, and therapeutic features following a course of adjuvant or neo-adjuvant treatments. Results: A total of 501 patients were eligible for this study (216 patients without VE vs. 285 patients with VE). The median follow-up was 274 (IQR: 195–523) days. In the group of patients with positive VE, the median age at diagnosis was 49 years, and the median progression-free survival (mPFS) was 881 (95% CI: 856, 1555) days; Patients with bilateral BC have a poorer mPFS of 515 (95% CI: 411, Not Estimable [NE]), while right BC was associated with a better outcome of 1,035 (95% CI: 869, NE) days (p = 0.001). Moreover, patients with positive hormonal receptors (HR >=10%) who benefited from endocrine therapies have a better PFS of 974 (95% CI: 872, NE) days compared to those with negative HR (<10%) of 656 (95% CI: 586, NE) days (p = 0.02). In addition to the molecular profile, TNBC was associated with poorer survival 579 (95% CI: 553, NE), compared to RH-/HER2+ 675 (95% CI: 635, NE), RH+/HER2- 935 (95% CI: 777, NE), and RH+/HER2+ 1,133 (95% CI: 856, NE) days (p < 0.001). Surgery was associated with better mPFS (935 (95% CI: 869, NE) days compared to neo-adjuvant or palliative patients 856 (95% CI: 635, NE) (p = 0.002). In the group of patients with negative VE, the median age was 48 years. The mPFS was 852 (95% CI: 789–996) days. Patients presented with positive lymph (N2) have a worse PFS of 611 (95% CI: 505, NE) days; in addition, patients with HER2=0 have a worse PFS of 775 (95% CI: 595, 1,320) days compared to HER2 1+ or non-amplified HER2 2+ 928 (95% CI: 840, NE) days, while no statistically significant differences between patients who received different treatment options (HER2 TKI, chemotherapy, radiotherapy, and endocrine therapy) were found. Conclusions: These findings emphasize the importance of considering VE status and hormonal receptor expression in tailoring treatment strategies for BC patients. Identifying high-risk individuals who may benefit from aggressive or novel therapies remains crucial for improving outcomes. Further research is warranted to validate these results and guide clinical decision-making.