bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of ruxolitinib and magrolimab on calreticulin in myelofibrosis CD34+ cells in vitro: Proof of concept for combination therapy.
Authors: Rinaldi Ciro Roberto , Boasman Kristian , Simmonds Matthew 
Published: August 2023

118 Background: In solid tumours, calreticulin (CALR) overexpression produces a pro-phagocytic signal and is counteracted by concomitant expression of anti- phagocytic CD47, reflecting an apoptosis vs survival mechanism. We have previously found that CD47, not CALR, is overexpressed on the membrane of patients with MPN. Anti-CD47 Magrolimab, is currently being evaluated in clinical trials in AML, MDS but have yet to be tested, either in monotherapy or in combination in MF. Methods: Mononuclear cells were collected by Ficoll separation from bone marrow of 6 MF patients and from 2 controls. CD34+ cells and monocytes were purified using Dynabeads kits from Thermofisher. Cells expression of CALR and CD47 was measured by flow cytometry, before and after incubation with ruxolitinib (Jak inhibitor) alone and in combination with magrolimab. Cells survival was calculated after combining CD34 with monocytes. Informed Consent was obtained for all samples collected. Results: CD47 membrane expression was 57% in untreated MF cells compared to 12% in the control samples and CALR membrane expression was 51.8% in untreated MF cell compared to 12.5% in the control samples. After incubation with ruxolitinib, MF CD34+ cell survival decreased to 98.2%. Following Incubation with magrolimab alone, MF CD34+ cells show no changes in survival (100% alive). The combination of ruxolitinib and magrolimab reduced slightly the MF CD34+ cell survival to 92%. A substantial membrane overexpression of CALR was observed in MF CD34+ cells when incubated with Ruxo and Magrolimab, 74.1%, vs Ruxo alone 52.6%, Magrolimab alone 53.4% and in untreated (51.8%). Interestingly, in the healthy controls, the exposure to combination therapy did not cause the same degree of CALR overexpression (20.7% vs 12.5%), indicating a much stronger pro-phagocytic effect following magrolimab/ruxolitinib combo in MF cancer cells. Conclusions: In vitro, treatment with ruxolitinib or ruxolitinib plus magrolimab, slightly reduce the overall cell survival rate in CD34+ MF samples, comparing with no significant changes in single agent magrolimab. However, the combination of Ruxolitinib and Magrolimab significantly increases CALR membrane expression comparing with Ruxo or Magrolimab alone, signalling a much stronger pro-phagocytic message in MF cells comparing with controls. The induced CALR over-expression, could stimulate a stronger immune response in vivo, where the presence of macrophages would allow removal of CALR rich cells and potentiate the cytoreductive activity towards MF clone. These data support the rational of combining Ruxolitinib with Magrolimab in the next clinical trial stage in myelofibrosis.
Preclinical development of ARD103, a CLL-1 CAR-T produced by a 3-day DashCAR technology, for acute myeloid leukemia.
Authors: Kuan Chien-Tsun , Huang Kao-Jean , Yang Jacob, Shun-Jen , Wu Tsung Han , Yeh Hom-Ming 
Published: August 2023

119 Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of the AML patients experienced primary refractory or relapse after current treatments, such as chemotherapy, hematopoietic stem cell transplantation, and targeted therapy. AML patients are in urgent need of novel therapeutic strategies. Leukemic stem cells (LSCs), which cause the treatment failure and leukemia relapsed. Human C-type lectin-like molecule-1 (CLL-1) is a surface antigen expressed on both AML malignant blast cells and LSCs, but not on normal hematopoietic stem cells, suggesting that CLL-1 is a compelling target with low off-tumor toxicity for novel AML treatment. Methods: ARD103 is a second-generation chimeric antigen receptor (CAR)-T cell, expressing a novel extracellular anti-CLL-1 scFv fused to a CD28 transmembrane domain, a CD28 co-stimulatory domain, and a CD3ζ activation domain. ARD103 was generated using lentiviral vector in an optimized 3-day DashCAR manufacturing process and demonstrated high percentage of CAR population (>80%), high percentages of memory T cells (Tscm and Tcm are >70%) and profound effector cytokine production (IFN-γ, granzyme A, perforin and granulysin). Results: ARD103, CLL-1 CAR-T exhibited specific killing on various CLL-1-expressing AML cell lines, such as U937, THP-1, and HL60, correlated to the levels of CLL-1 expression. In the AML U937-Luc xenograft mouse model, the CLL-1 CAR-T cells prolonged the survival time significantly (p < 0.0001), with superior CAR-T cell persistence, to the end point of the study at 48 days compared to the median survival time at 23 days in the untreated or control groups. Furthermore, the xenograft mice receiving as minimum as 3 x105 CAR-T cells per mouse were able to elicit effective recall responses after tumor rechallenge and survived for more than 60 days. The off-target binding interactions of ARD103 CAR-T cells using a human cell microarray showed a specific and strong interaction with CLL-1 but not with other human membrane/extracellular proteins. In the aspect of on-target off-tumor toxicity, the hematotoxicity assessment on ARD103 exerted modest (5%-23%) or no effect on colony formation inhibition of CD34+ cells derived from human normal bone marrow or peripheral blood, respectively. Furthermore, autologous ARD103 cells were successfully prepared from relapsed/refractoryAML patients and demonstrated to mediate specific cytotoxicity to primary AML blasts and LSCs derived from the same patients. Conclusions: Taken together, the ARD103 CLL-1 CAR-T candidate has demonstrated excellent anti-AML potency and efficacy with minimal safety concerns, and warrant to be further developed preclinically and clinically for the treatment of relapsed/refractory AML patients. Keywords: Acute myeloid leukemia; CLL-1; Chimeric antigen receptor-T cell; Immunotherapy.
Clinical applications of measurable residual disease monitoring by multi-parametric flow cytometry and next-generation sequencing in B-cell precursor acute lymphoblastic leukemia.
Authors: Lee Gun-Dong , Ahn Ari , Lee Jong-Mi , Kim Myungshin 
Published: August 2023

121 Background: Minimal residual disease (MRD) is accepted as the strongest independent prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The most frequently used methods for MRD monitoring include multi-parametric flow cytometry (MFC) and next-generation sequencing (NGS)-based IGH/IGK gene rearrangement. Both methods have been described to reach a low sensitivity threshold and be broadly applicable to most patients with BCP-ALL, although the clinical MRD cut-off of the two methods has not been fully defined. In this study, we compared MFC-MRD and NGS-MRD and established their clinical cut-off in BCP-ALL. Methods: Bone marrow aspirates with less than 5% blasts were obtained from 117 treated BCP-ALL patients. MFC-MRD assessment was performed using DuraClone RE ALB tubes (Beckman Coulter, Marseille, France) modified by adding 5 additional antibodies. In total, up to 1×105 cells were acquired using DxFLEX flow cytometer (Beckman Coulter), and all acquired data were analyzed using the Kaluza software v2.1. NGS-MRD was performed using the LymphoTrack IGH and IGK assay panels (InVivoScribe, San Diego, CA). We amplified 240 ng of high-quality DNA with a single multiplex master mix containing primers, and the library DNA was denatured and loaded onto a Miseq reagent kit v2. The FASTQ files were analyzed using the LymphoTrack MRD software v2.0.2. MRD evaluated using both of MFC and NGS in each sample, and the virtual sensitivity of both methods was 10-5. For 84 patients available, we analyzed the relapse-free survival (RFS) and overall survival (OS) rate for each MRD status and established a clinical cutoff. Results: We found a high correlation between methods (r=0.640) and a concordance rate of 81.2% for detecting MRD at 0.01% level. An MRD value of 0.01% proved to be a significant threshold value for 1-year RFS and OS. There was a difference in prognosis in both RFS and OS, but statistical significance was found only in RFS (MFC-MRD: 93.4±3.2% for MRD <0.01% vs. 37.5±27.3% for MRD ≥0.01%, P=0.007; NGS-MRD: 93.7±3.6% for MRD <0.01% vs. 68.8±14.2% for MRD ≥0.01%, P=0.016). In a Kaplan-Meier estimate of RFS at a threshold of 0.01%, patients who were negative for MRD by MFC and positive by NGS (n=12) had an intermediate prognosis between patients who were negative by both MFC and NGS (n=55) and patients who were positive by both MFC and NGS (n=11) (98.14±3.2%, 83.34±10.8%, 40.94±29.5%, respectively, P=0.017). Conclusions: An MRD threshold of 0.01% for both MFC and NGS is reasonable for clinical identification of poor-risk patients. NGS-MRD detection improves risk stratification for BCP-ALL.
The evolution of an oncology site network partnership in a COVID era clinical trial environment.
Authors: Helou Sarah , Vidhyarkorn Tanya , Churchill Sarah , Russell Janice 
Published: August 2023

125 Background: As a leader in cancer therapy research, Roche created the immunotherapy Centers of Research Excellence (imCORE) Network, a worldwide research network designed to connect members in an open environment of shared information, expertise, and decisions. This network is dedicated to advancing the comprehension of the underlying science and shared operational challenges in order to accelerate the most promising new treatment options for patients. Pre-pandemic the imCORE network was an established partnership model leader with several years of experience. Relationships between site and sponsor were established and consistent. Regularly cadenced face to face and virtual meetings provided proven pathways for open communication and collaboration opportunities. A pipeline of operational efficiencies, pain point interventions, best practices and strategies were brainstormed, co-created, and implemented across multiple workstreams. COVID arrived in March of 2020 and over the course of the next months to years the world changed. These changes were felt acutely, directly impacted clinical research, and specifically impacted imCORE sites, their patients, the network, and how it operates. Methods: This paper focuses on the Roche Sponsored clinical trial operational excellence aspects of the network. Data is collected from network sites related to pre and "post" COVID priorities and impacts. The data is then analyzed to produce best practice recommendations for oncology research sites and networks. Results: It highlights the direct impacts of COVID to a sponsored trial site network. This includes specific measures the network has taken to evolve to fit the needs of its sites and their patients and presents a pathway forward for site networks to consider in the new reality of COVID era clinical trials. Conclusions: COVID impacted and continues to impact clinical research sites and sponsored trial networks in significant and lasting ways. Site and network operations need to evolve to meet the needs of patients and staff in this new reality.
Associations of wearable tracker use with physical activity and health outcomes in patients with cancer: Findings from the HINTS-SEER (2021).
Authors: Pu Junlan , Cho Youmin 
Published: August 2023

131 Background: Physical inactivity is a global issue for cancer survivors. Wearable trackers are promising to address physical inactivity by providing real-time feedback on physical activity (PA) and offer opportunities for self-monitoring and goal setting. Meta-analysis has reported the effects of interventions that incorporate wearable trackers on improved physical inactivity and related health outcomes (e.g., BMI, anxiety and depression, and self-rated health). However, wearable trackers were often used an an adjunct to PA interventions, and the effectiveness of wearable trackers alone is unknown. The aim of this study was to determine the association of wearable trackers with PA and health outcomes (BMI, anxiety and depression, and self-rated health) in patients with cancer, using a national dataset. Methods: Data from 957 cancer survivors from Health Information National Trends Survey – Surveillance, Epidemiology, and End Results Program (HINTS-SEER-2021) were analyzed. The outcome variables examined were: time spent in moderate to vigorous physical activity (MVPA), weekly frequency of strength training, BMI, anxiety/depression levels, and self-assessed health status. The primary independent variable was whether cancer survivors had used wearable devices within the past 12 months. Design-based linear regression for continuous outcome variables and ordinal logistic regression for ordinal outcome variables were conducted to determine the associations, after controlling for sociodemographic, cancer-related clinical (i.e., type, stage, time since diagnosis), and general health-related factors (i.e., BMI and smoking). All data analyses accounted for the complex survey design and sample weights. Results: Only 28% of cancer survivors reported wearable devices use. Bivariate analyses showed younger age, higher income, and employed status were significantly associated with wearable tracker use ( P<.001). Wearable devices use was significantly associated with higher time spent in MVPA (b=37.94, 95% OR:8.38, 67.5; P=.01), more frequent strength training per week (adjusted OR=1.50, 95% OR: 1.09, 2.06; P=.01), and better self-rated health status (adjusted OR=1.58, 95% OR:1.09, 2.29; P=.01), but not associated with BMI or anxiety/depression. Conclusions: This study suggests that the uptake of wearable devices is low and highlights the digital divide among patients with cancer. This study has confirmed the associations of wearable tracker use with PA and self-rated health, supporting using wearable trackers as a promising tool to facilitate PA promotion.
The response rates to surveys among breast cancer patients using different manners of distribution: A prospective study of integrated rehabilitation.
Authors: Kurir Borovcic Mateja , Mavric Zlatka , Mozetic Anamarija , Zagar Tina , Zadravec Zaletel Lorna , Kozjek Nada Rotovnik , Mlakar Mastnak Denis , Borstnar Simona , Besic Nikola 
Published: August 2023

138 Background: Communication with breast cancer patients is crucial within individualised integrated rehabilitation, where the patients are at the centre of the provided health care services. Anonymous surveys could be used as one of the tools to check the needs of patients, the effectiveness of various aspects of the interventions offered and to obtain valuable feedback from patients. Our aim was to determine which manner of conducting anonymous surveying among breast cancer patients would be most suitable for improving the health service of individualized integrated rehabilitation. Methods: The subjects of our prospective study were 600 females (29-65 (mean 52) years of age), who participated in the pilot study on the individualized integrated rehabilitation of breast cancer patients receiving treatment at Institute of Oncology Ljubljana in 2019-2022. Questionnaires of implemented surveys were anonymous with different manners of distribution and on three different topics. The first survey was conducted via standard post sending questionnaires on papers to the patients to inquire about their satisfaction with the provided services after the conclusion of their treatment. The second survey was conceded via email, sending online questionnaires to inquire about appropriateness of interventions and patients' opinions about spa treatment. The third survey was conducted half via email and half via text message on mobile phone (SMS) to inquire about the most suitable terms of the regular physical activity during oncological treatment. The survey response rate was calculated as the number of valid surveys received (numerator) divided by the number of surveys distributed (denominator). If all questions were not answered, the survey was invalid. Results: There was a significant difference in the response rate of the patients to the anonymous surveys, depending on the manner of distribution of the survey. The response rate of patients who got questionnaires by regular mail were 51%, 28% and 13% if received by e-mail and 27% if sent via SMS. The difference in the response rate in the survey on physical activity, received by email or by SMS, was statistically significant (p= 0,0026). Conclusions: The highest response rate of breast cancer patients was received by sending the questionnaires via regular post. Clinical trial information: V3-1906. [Table: see text]
Clinical impact of discrepancy in PD-L1 expression on tumor cells between 22C3 and SP142 assay on the efficacy of pembrolizumab in advanced NSCLC patients.
Authors: Miyakoshi Jun , Yoshida Tatsuya , Shirasawa Masayuki , Torasawa Masahiro , Matsumoto Yuji , Masuda Ken , Kashima Jumpei , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Shiraishi Kouya , Kohno Takashi , Yatabe Yasushi , Yamamoto Noboru , Ohe Yuichiro 
Published: August 2023

145 Background: Pembrolizumab and atezolizumab monotherapy has been the standard of care in treatment-naïve advanced NSCLC with high PD-L1 expression. On the other hand, the evaluation of PD-L1 expression as companion diagnostics is different between two agents (Clone: 22C3 and SP142). PD-L1 Immunohistochemistry Comparability Study showed that the SP142 assay showed significantly less sensitivity to detect PD-L1 expression on TCs, leading to the discrepancy in cases with PD-L1 high expression on tumor cells (TCs). This study aimed to evaluate the clinical impact of the discrepancy in PD-L1 high expression on the efficacy of pembrolizumab monotherapy in advanced NSCLC patients. Methods: We retrospectively reviewed advanced NSCLC patients with PD-L1 high expression (22C3: TPS ≥ 50%) who received first-line pembrolizumab monotherapy, and had sufficient tumor tissues for evaluating PD-L1 expression on TCs (SP142). Additionally, RNA-sequence analysis was performed to evaluate the biological differences in the discrepancy cases with PD-L1 high expression on TCs. Results: A total of 45 patients (PD-L1 expression TPS [22C3]: ≥ 50%) were included. Of these patients, 5 / 9 / 18 / 13 patients had PD-L1 expression (SP142): TC 0 / 1 / 2 / 3, respectively. The objective response rate (ORR) and median PFS (mPFS) of pembrolizumab in all pts were 62% (95% confidence interval [CI], 47-76) and 7.52 months (mo, 95% CI, 4.73-10.97). The ORR and PFS in patients with TC ≤ 1 were significantly worse than those with TC ≥ 2 (TC ≤ 1 vs. TC ≥ 2: ORR 21% vs. 81%, p < 0.001, and mPFS 3.81 mo vs. 8.05 mo, p = 0.004, Table). In patients with PD-L1 TPS ≥ 90% (n = 34), the ORR and PFS in patients with TC ≤ 1 were also significantly worse than those with TC ≥ 2 (TC ≤ 1 vs TC ≥ 2: ORR 0% vs. 82%, p < 0.001, and mPFS 2.04 mo vs. 10.97 mo, p < 0.001, Table). Additionally, RNA-sequence analysis showed that tumors with TC ≤ 1 had significantly suppressed immune-related pathways (ALLOGRAFT REJECTION and IFNG RESPONSE) and significantly lower T-cell-inflamed gene expression profiles compared with those with TC ≥ 2. Conclusions: Discrepancy in PD-L1 expression on tumor cells between 22C3 and SP142 assay was a negative predictive factor for pembrolizumab monotherapy and showed suppressed tumor microenvironment.[Table: see text]
Characteristics of Met gene and its relationship with immune index TMB/MMR genes/DDR genes in Chinese NSCLC population.
Authors: Zhang Hongying , Liu Zikai , Feng Libao , Xu Yan , He Hongsheng , Luo Peng 
Published: August 2023

147 Background: Patients with driver gene mutations in NSCLC can benefit significantly from corresponding targeted therapy, but respond poorly to immunotherapy (such as EGFR, ALK). As a driver gene of NSCLC, the relationship between the characteristics of Met and many immune indicators in the Chinese population is still unclear. This study aims to elucidate the characteristics of the Met gene and its relationship with immune indicators in the Chinese NSCLC population. Methods: 732 Formalin-Fixed Paraffin-Embedded (FFPE) lung adenocarcinoma samples were collected and detected by Next Generation Sequencing 603-gene panel from July 31, 2021 to March 14, 2023 were selected from the study. The biomarkers of immunotherapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 22C3 [TPS], DDR-related genes (ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, MRE11, PALB2, RAD50, RAD51C, RAD51D) and MMR-related genes (MLH1, MSH2, MSH6, PMS2) were also calculated. Results: Among the 732 subjects included in the previous detection, a total of 32 cases were detected to carry Met-related gene mutations. The detection rate of Met gene was 4.37%, which was consistent with the mutation probability of Met mutation of 4-6% in previous studies. The median age was 65 (13-97). 81% of patients belonged to mutations of unknown clinical significance (26/32); 15% of patients belonged to exon 14 skipping type (5/32); Met amplification accounted for the least, accounting for only 6% (2/32 ). The top 3 loci of mutation frequency were Met_L221W (4/32), MET_Q1067K (2/32), and MET_F206S (2/32). The gene partners of Met co-mutation were analyzed, and the top five genes were PPP2R1A, HIST1H3G, CDKN1B, SYK, and ERBB4. In the analysis of the immune indicators of the Met mutant population and the Met wild-type population, the Mann-Whitney U test found that among the TMB indicators, the mean value of the Met group was 8.09 with a standard deviation of 7.91, and the mean value of the un-Met group was 5.94 with a standard deviation of 4.98. Met was correlated with TMB with statistical difference (P value 0.02). Among the MSI indicators, the mean value of the Met group was 8.16, and the mean value of the un-Met group was 7.76. The correlation between Met and MSI status was not significant. We also paid attention to Met and DDR-related genes and MMR-related genes. Mann-Whitney U analysis showed that there was no significant correlation between MET group and wild-type MET group and DDR gene (p-value: 1.0), but there was a significant relationship between MET group and wild-type MET group and MMR gene (p-value: 0.026). Conclusions: In the Chinese NSCLC population, there is a correlation between Met expression and TMB, and the Met mutation will increase the TMB value. Met expression was significantly correlated with MMR-related gene mutations.
Genomic predictors for early recurrence of hepatocellular carcinoma (HCC) after curative resection.
Authors: Huang Lisha , Zhang Shuilong , Kai Zhentian , Xu Yan 
Published: August 2023

157 Background: Early recurrence of HCC after curative resection is common. However, the association between genetic alterations and early HCC recurrence, especially in Chinese patients (pts), remains largely unknown. Methods: We retrospectively analyzed 214 formalin-fixed paraffin-embedded (FFPE) tumor specimens of HCC patients that were collected from June 2016 to October 2021. Clinical outcomes related to frequently mutated genes were evaluated in 176 pts with a median follow-up time of 21.9 months. Tumor tissue samples were detected by OncoDrug-Seq 603-gene panel assay through next-generation sequencing. Early recurrence was defined as the appearance of an intra- or extrahepatic tumor nodule within 1 year of curative resection. Results: In multivariate analysis, three tumor suppressor genes related to early recurrence, namely PRDM1, NOTCH3, and MGA. PRDM1 mutations and NOTCH3 mutations were the risk factor for early recurrence (＜1 y after surgical resection) (hazard ratio (HR), 4.22; 95% confidence interval (CI), 1.96-9.06; p＜0.001 ) (HR, 2.96; 95% CI, 1.43-6.13; p=0.003). These two mutated genes were also significantly associated with overall survival (HR, 3.39; 95%CI, 1.23-9.34; p=0.018) (HR, 5.22; 95%CI, 2.10-12.99; p＜0.001). We found a trend toward an increased risk of early recurrence in pts with MGA mutation. (HR, 2.06; 95%CI, 1.05-4.05; p=0.027). Conclusions: Mutations in these three tumor suppressor genes were shown to be shorter time intervals to relapse after curative resection. We also demonstrated that pts who have these markers require more frequent monitoring and follow-up visits.