bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Insights into the Link between Rheumatoid Arthritis and Malignant Lymphoma: A Multi-Stage Study of Observational and Genetic Analyses
Authors: Yu Xinghao , Chen Yiyin , Lei Lei , Lu Huimin , Chen Jia , Fan Yi , Wu Depei , Xu Yang 
Published: December 2024

Objective To investigate complex relationship between rheumatoid arthritis (RA) and malignant lymphoma (ML).
Methods Prospective analysis was conducted in participants from UK Biobank to evaluate associations between RA and subsequent ML risk. We estimated genome-wide genetic correlations by utilizing publicly available European genome-wide association (GWAS) summary statistics. Then cross-trait pleiotropic analysis was performed to identify shared signals and genes. Functional annotation, tissue-specific and cell-specific analysis were performed to determine biofunctions of shared genetic signals. Finally, two-sample Mendelian randomization (MR) was conducted to explore causal interactions between diseases.
Results Our results demonstrated strong positive associations between RA and ML and its subsets both in epidemiological and genetical evidence. Cross-trait pleiotropic analysis identified 20 shared loci (e.g., 11q23.3 and 20q13.12) with high colocalization evidence, which could be mapped to 67 pleiotropic genes, such as CD40, ITPR3, TNFRSF14 and MAPK3. CD40 was found to increase the risk of RA but reduce the risk of lymphoma. MAPK3 was identified as a potential drug target for both RA and lymphoma. Genome-wide gene-set enrichment analysis revealed shared mechanisms between different trait pairs, particularly in pathways related to B cell activation and T cell selection. Functional enrichment of pleiotropic genes highlighted lymphocyte proliferation, activation, and chromatin remodeling. These sharing mechanisms may be at work in tissues such as whole blood, spleen, terminal ileum, and EBV-transformed lymphocytes. We also identified co-localization evidence and enrichment in multiple immune cell subsets, especially B cells and T cells. Finally, MR analysis confirmed that RA onset increases the risk of lymphoma.
Conclusions These results support the shared genetic basis underlying RA and ML and have important implications for identifying potential intervention and druggable targets.
Effect of Efgartigimod IV on Immature Platelet Count Fraction in Primary Immune Thrombocytopenia
Authors: Matthijssens Filip , Miyakawa Yoshitaka , Nishiwaki Kaichi , Ayguasanosa Jaume , Lan Lan , Hultberg Anna , Ulrichts Peter 
Published: December 2024

Immature platelet fraction (IPF%) is the number of immature platelets (PLT) relative to total PLT number and is a measure for enhanced PLT degradation. IPF% is increased in patients with primary immune thrombocytopenia (ITP) and in some countries, such as Japan, it is used as part of the ITP diagnostic criteria. ITP is a bleeding disorder caused by accelerated PLT destruction and impaired production facilitated in part by autoantibodies. Efgartigimod is a human IgG Fc fragment engineered to bind competitively to the neonatal Fc receptor (FcRn) with high affinity, preventing endogenous IgG recycling and reducing IgG levels, including pathogenic IgG autoantibodies. In 2024, intravenous (IV) efgartigimod was approved for the treatment of patients with chronic primary ITP in Japan.
Efficacy and safety of efgartigimod IV were evaluated in ADVANCE IV (NCT04188379), a phase 3, multicenter, double-blinded, placebo-controlled trial in adults with persistent and chronic primary ITP. Participants with an average of 2 PLT counts &lt;30×109/L during screening were randomized to efgartigimod IV 10 mg/kg or placebo. Primary endpoint was the proportion of chronic ITP participants with a sustained PLT count response (defined as PLT counts of at least 50×109/L for at least 4 of the 6 visits between Weeks 19 and 24 of the study). IPF% was also measured as exploratory research to evaluate the effects of efgartigimod on PLT turnover. IPF% was measured locally in facilities equipped with a hematology analyzer that could determine this platelet subset.
In ITP participants (N=131), sustained PLT response was demonstrated in more efgartigimod IV-treated participants (25.6%) than placebo (6.7%; P=0.0108). In the 40 participants of which immature platelets were measured, mean [±SE] IPF% was reduced following efgartigimod IV treatment (baseline IPF%, 21.6 [±2.6]; Week 24 IPF%, 13.6 [±2.7]) while no decrease was noted for placebo (baseline IPF%, 29.2 [±5.3]; Week 24 IPF%, 33.8 [±4.5]).
Observed PLT count responses in efgartigimod IV-treated participants with primary ITP are likely mediated by a reduction in PLT degradation.
Copy Number Variants Identified By Shallow Whole-Genome Sequencing in Multiple Myeloma
Authors: Li Jiali , Xiang Xixi , Rao Jun , Zhou Sha , Zeng Yunjing , Zhang Xi , Gao Li 
Published: December 2024

Background:
Multiple myeloma is a plasma cell neoplasm driven by primary and secondary chromosomal events. The detection of these copy number abnormalities (CNAs) are important, because they affect the prognosis, therapeutic response and disease survival.
Methods:
A total of 131 patients with newly diagnosed multiple myeloma were enrolled in this study to detect genome-wide CNAs by shallow whole-genome sequencing(sWGS). Risk stratification was performed following the Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART) criteria.
Results:
Compared with karyotyping and Fluorescence in situ hybridization (FISH), sWGS
significantly improved the detection rate of CNAs from 7.8% and 43.7%, respectively, to 75.6%. sWGS provided new CNA information for 75.6% of the patients, and changed the risk stratification for 19.1% of patients according to mSMART criteria. The concordance rate between sWGS and FISH in detecting the four conventional loci (1q21 gain, 13q14 del, 13q14.3 del, and 17p13 del) was 80.2%. A high concordance was observed in CNA between matched bone marrow and peripheral blood samples.
Conclusion:
sWGS can be regarded as an automated, convenient and cost-effective approach to describe genomic CNA profiles. With the advantage of detecting CNAs of short segments and incorporating routine diagnostic methods, sWGS can add value to conventional karyotyping with improved prognostic stratification.
Enhancement of mTORC1 Activity in Engineered Therapeutic CD4+ T Cells Amplifies Tumour Infiltration but Impairs Cytotoxicity
Authors: Sillito Francesca Emily , Holler Angelika , O'Neill Aideen T , Callender Lauren A , Henson Sian M , Stauss Hans , Chakraverty Ronjon 
Published: December 2024

There is substantial interest in developing strategies to improve the intrinsic functions of engineered therapeutic T cells, for example by manipulating their metabolic fitness. Mammalian target of Rapamycin complex 1 (mTORC1) is a critical orchestrator of anabolic metabolism and effector functions in T cells. Our group has previously shown that overexpression of an mTORC1 positive regulator (Ras homologue enriched in brain; Rheb) in engineered CD8+ T cells increased anabolic metabolism, improved tumour infiltration and cytotoxicity, but reduced their long-term persistence (1). However, because of differences in baseline and activation-induced metabolism, it is less clear how manipulation of intrinsic mTORC1 activity might influence therapeutic CD4+ T cell function.
We therefore tested the consequence of overexpressing Rheb in a murine model of anti-tumour immunity that requires in vivo cytotoxic CD4+ T cell differentiation. As we have previously found for CD8+ T cells, Rheb overexpression in tumour-specific CD4+ T cells, engineered to express a class II restricted T cell receptor targeting melanoma antigen Tyrosinase-related protein- 1 (TRP-1), enhanced baseline and activated glycolysis and oxygen phosphorylation, promoted differentiation of T-bet high effector cells and significantly increased tumour infiltration in vivo. Conversely, mTORC1 inhibition using Proline-rich Akt substrate of 40kDa (PRAS40) produced a state of relative metabolic quiescence, rendered the cells in a less differentiated Th0 state and reduced tumour infiltration. Rheb-transduced tumour-specific CD4+ T cells showed reduced cytotoxic gene expression and failed to eliminate all tumours compared to control cells. Unlike CD8+ T cells, constitutive mTORC1 activation did not impair long-term persistence of CD4+ T cells, but the surviving cells expressed high levels of co-inhibitory receptors, especially Lymphocyte-activation gene 3 (LAG-3), and showed impaired proliferation in responses to antigenic re-challenge.
Together, these data highlight the need to address how engineering of intrinsic metabolic fitness might impact upon CD4+ versus CD8+ T cells in distinct ways and suggests the need for bespoke strategies to enhance their respective functions and survival.
References Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation. Veliça P, Zech M, Henson S, Holler A, Manzo T, Pike R, Santos E Sousa P, Zhang L, Heinz N, Schiedlmeier B, Pule M, Stauss H, Chakraverty R. 2015 Jul, Cancer Res. , pp. 1;75(13):2641-52.
A Prospective, Open-Label, Multicenter, Randomized Controlled Study Comparing the Efficacy and Safety of Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Combined with Orelabrutinib/Chidamide/Venetoclax/Lenalidomide/Penpulimab (Pola-RCHP-X) Versus RCHOP-X and Pola-Rchp in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma
Authors: Liang Jinhua , Wang Li , Shen Haorui , Yin Hua , Wu Jiazhu , Li Yue , Pan Bihui , Zhang Xinyu , Kong Yilin , Li Jianyong , Wei Xu 
Published: December 2024

Background and Significance
In recent years, most phase III clinical trials exploring first-line treatments for diffuse large B-cell lymphoma (DLBCL) have ended in failure, with the notable exception of the POLARIX study. This may be primarily due to the heterogeneity of DLBCL. Currently, the Pola-R-CHP regimen has emerged as one of the new standard first-line treatments for DLBCL. Given the heterogeneity of DLBCL, combining different therapeutic agents tailored to specific genetic subtypes may be a strategy to further improve first-line treatment efficacy. Therefore, we are planning to conduct a prospective, multicenter, randomized controlled trial to comparing the efficacy and safety of Pola-RCHP-X versus R-CHOP-X or Pola-R-CHP (NCT06516978).
Study Design and Methods:
This study aims to enroll 528 patients aged 18-80 years with an International Prognostic Index (IPI) score of 2-5, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, diagnosed with CD20+ DLBCL, and who have not received prior systemic treatment. Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the following three arms: Pola-RCHP-X, R-CHOP-X, or Pola-R-CHP.
Patients in the Pola-RCHP-X and R-CHOP-X arms will first receive one cycle of Pola-R-CHP or R-CHOP while undergoing genetic subtyping. From cycles 2 to 6, patients with MCD, BN2, or N1 subtypes will receive Pola-RCHP-orelabrutinib/ R-CHOP-orelabrutinib; those with the EZB-MYC+ subtype will receive Pola-RCHP-venetoclax/ R-CHOP-venetoclax; those with the EZB-MYC− subtype will receive Pola-RCHP-chidamide/R-CHOP-chidamide; those with TP53 mutations will receive Pola-RCHP-penpulimab/R-CHOP-penpulimab; and those with the ST2 subtype or NOS will receive Pola-RCHP-lenalidomide/R-CHOP-lenalidomide. This will be followed by two cycles of Rituximab monotherapy. Patients in the Pola-R-CHP arm will receive the standard 6 cycles of Pola-R-CHP followed by 2 cycles of Rituximab.
The primary endpoint of the study is progression-free survival at 24 months (PFS24) as assessed by the investigators. Secondary endpoints include investigator-assessed complete response (CR) rate, overall response rate (ORR), event-free survival (EFS), overall survival (OS), and safety.
Combination of All-Trans Retinoic Acid Resumes the Sustained Response of TPO-RA in ITP
Authors: Fan Wenxuan , Ye Jieyu 
Published: December 2024

Sustain response off treatment (SROT) is the therapeutic goal for idiopathic thrombocytopenic purpura (ITP) patients treating by thrombopoietin receptor agonist (TPO-RA). Although the majority patients have therapeutic response during TPO-RA treatment, platelet counts may fluctuate in some cases. Researches showed that sustained and stable platelet response is one of the important conditions to achieve SROT.
All-trans retinoic acid (ATRA) has shown significant effects in treating ITP. Our study found that platelet fluctuation by TPO-RA treatment can be resumed by short term combined use of ATRA. In order to investigate whether Combination of all-trans retinoic acid resumes the sustained response of TPO-RA in ITP.
We enrolled 17 ITP patients from January 2023 to July 2024 in Nanfang hospital. Two of them were excluded because of insufficient treatment duration due to severe headache. Therefore, data from 15 patients were finally included. We defined platelet fluctuation as platelet numerical difference more than 100×109/L within one month. Oral dose of ATRA was 20mg once daily. Adverse events were monitored and assessed according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE5.0).
At baseline, the ratio of male vs. female was 2:13. The median age was 38 (range=22-64). The types of TPO-RAs used were: Eltrombopag 46.67% (7/15), Avatrombopag 26.67% (4/15), Hetrombopag 26.67% (4/15). The median time of ATRA treatment was 94 days (range=49-153). The efficiency rate of ATRA in resuming platelet response was 86.67% (13/15). Side-effects of ATRA in 15 patients were tolerable. The rate of dry and cracked lips was 13.33% (2/15). The rate of headache was 6.67% (1/15). The rate of hair loss was 13.33% (2/15). The rate of rash was 6.67% (1/15).
Our data shows that short-term treatment of ATRA in ITP during platelet fluctuation by TPO-RA may be effective and safe.
Daratumumab for Treatment of Epstein-Barr Virus-Associated Post -Transplant Lymphocyte Proliferative Disease after Rituximab Treatment Failure
Authors: Li Gang , Yang Donglin , Feng Sizhou , Jiang Erlie , Liu Xin , Liang Chen , He Yi 
Published: December 2024

Aims: To explore a new method for treating failure of rituximab plus immunosuppressant dose reduction in EB virus-related post-transplant lymphoproliferative disorders (PTLD).
Methods: This study retrospectively analyzed the clinical data of 60 patients diagnosed with PTLD at the Institute of Hematology & Blood Diseases Hospital and Chinese Academy of Medical Sciences from May 2017 to June 2024, including confirmed and clinically diagnosed cases. Among them, 22 patients underwent lymph node biopsy, and except for 3 patients whose biopsy specimens were not marked with CD38, the remaining 19 patients had positive CD38, of whom 10/19 were strongly positive. We treated 4 patients with failed rituximab plus immunosuppressant dose reduction therapy (1 case of acute T-cell leukemia, 1 case of acute myeloid leukemia, 1 case of acute B-cell leukemia, and 1 case of Ph+ mixed cell leukemia) with daratumumab.
Results: Of the 4 patients, 3 had obvious disease progression after receiving rituximab 375mg/m2/w twice (EBV-DNA progressively increased to more than 100 times the baseline level or lymph nodes progressively enlarged), and 1 had an initial EBV-DNA level of 107,310 copies/ml, which increased to 354,787 copies/ml after receiving rituximab. All 4 patients received daratumumab 16mg/kg qw 2-4 times, and all patients achieved complete remission (CR). They were followed up for 2.5 to 22.5 months, and all patients were alive and in complete remission from PTLD. 2/4 patients experienced a clear viral infection after receiving the CD38 monoclonal antibody, including one case of widespread adenovirus infection and one case of herpes simplex virus infection in the mouth, nose, and eyes, which improved after treatment.
Conclusion: This study is the first to reveal high expression of CD38 in PTLD and successfully treated 4 patients who failed to reduce their treatment with rituximab and immunosuppressants. Daratumumab may become a new option for the treatment of PTLD patients.
Early Detection of Immune-Dysregulation Predicts a Better Response to Immunosuppressive Treatment in Chronic Immune Thrombocytopenia
Authors: Palmisani Elena , Dell'Orso Gianluca , Del Bò Erica , Giarratana Mariacarla , Arcuri Luca , Guardo Daniela , Bagnasco Francesca , Grossi Alice , Lanciotti Marina , Terranova Paola , Dufour Carlo , Fioredda Francesca , Miano Maurizio 
Published: December 2024

Introduction: chronicimmune thrombocytopenia (ITP) is a highly heterogeneous condition in terms of clinical course and response to treatment and it could represent the epiphenomenon of a complex immune-dysregulation process. Not all patients respond with equal effectiveness to different therapeutic approaches. However, specific indicators to predict therapeuthic response to the most suitable second-line therapy (mycophenolate mofetile, sirolimus and TPO agonists) in the acute phase have not yet been identified.
Aims: to describe the clinical and immunological features and the treatment response in order to identify a group of clinical and immunological variables predictive of a response to a specific second-line therapy.
Methods: 72 paediatric patients with persistent or chronic ITP followed at Haematology Unit, Gaslini Children Hospital have been reviewed retrospectively. Our patients present a baseline assessment with extended analysis of lymphocyte subpopulations (immunophenotype), and a follow up of at least 6 months. In this cohort, 51 patients also have an assessment of response to a second-line therapy.
Results: signs of immune-dysregulation in the aute phase, such as an increased in double T negative lymphocytes (DNT), defined according to ALPS NIH 2009 criteria (&gt;1,5%), a reduced in T-CD4 cells and NK cells compared to age reference values (rispectively p=0.05, 0&lt;0.05 and p&lt;0.05) and the simultaneous presence of ¾ positive parameter of the ALPS panel (DNT, T lymphocytes B220, memory B lymphocytes CD27 and CD3+CD25+/HLADR+ ratio) (p&lt;0.05) predict a better response to immunomodulatory therapy than TPO agonists.
Conclusion: an early immonophenotypic characterisation at diagnosis represent an excellent tool to identify the best second-line therapy (immunomodulators or TPO-agonists); it is also crucial to guide an early indication to perform genetic studies in order to orientate the use of a possible target therapies.
The Prognostic Value of Dynamic Minimal Residual Disease after Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma in Novel-Agent Era: Long-Term Follow-up
Authors: Yang Guangzhong , Gao Wen , Chen Wenming 
Published: December 2024

ABSTRACT
Objective: To investigate the clinical prognostic value of dynamic minimal residual disease (MRD) after autologous hematopoietic stem cell transplantation (AHSCT) in patients with multiple myeloma (MM).
Methods: Patients with MM who underwent AHSCT in Beijing Chao-Yang Hospital from February 2016 to December 2019 were enrolled in this study. All the patients in the study had complete baseline data at the diagnosis. AHSCT was performed after induction chemotherapy. Response evaluation was performed after induction therapy. All the patients were assessed at approximately 100 days after AHSCT. Bone marrow MRD by NGF was performed every three months and dynamically monitored for at least 12 months. All the patients were divided into different groups according to cytogenetics and MRD status. Survivals in different groups were analyzed by IBM SPSS 22.0 statistical software.
Results: A total of 150 patients with MM were enrolled in this study at last, including 66 patients in the cytogenetic standard risk group and 84 patients in the cytogenetic high-risk group. The median age was 54 years (range 30-68 years) and 87 male patients (58.0%) was in the study.
The median follow-up was 52 months. Patients in the standard-risk group had better clinical prognosis than those in the high-risk group [median PFS in the standard-risk group was not achieved, and median PFS in the high-risk group was 45 months (P&lt;0.001); the estimated 5-year OS rate of the standard-risk group and the high-risk group was 90.3% and 66.7%, respectively (P=0.001)].
According to MRD status of patients, patients in each group were divided into three subgroups: persistent positive (Ppos), transient negative (Tneg) and persistent negative (Pneg). The median OS and median PFS of all subgroups in the standard-risk group was not reached (P=0.118 and P=0.229). In high-risk group, the median OS of MRD Pneg subgroup was not reached, and the estimated 3-year OS rate was 100%; The median OS of MRD Ppos subgroup was 78 months, and MRD Tneg subgroup only 34 months (P&lt;0.001) (Figure 1a); the median PFS of MRD Pneg group was not reached, and the estimated 6-year PFS rate was 69.0%; median PFS of MRD Ppos subgroup was 28 months, and MRD Tneg subgroup only 10 months (P&lt;0.001) (Figure 1b).
Conclusions: MRD Pneg might overcome the adverse prognosis of MM patients with high-risk cytogenetics.
Figure 1a: Overall survival of pts with HRMM in different subgroups
Figure 1b: progression-free survival of pts with HRMM in different subgroups
Pharmacokinetic and Dose Response Relationships Observed in the Study “a Phase 1, Open- Label Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTX-100 in Patients with Advanced and Relapsed/Refractory T Cell Lymphoma”
Authors: Chew Terrence , Mansour Mariam , Fernando MALAVER ORTEGA Luis , Bahadure Upaly , Yannakou Costas K. , Yatomi-Clarke Steven Lee , Prince H. Miles 
Published: December 2024

PTX-100 is a small molecule inhibitor of GGT-1 that disrupts the oncogenic activity of RAS pathways by inhibiting post-translational modification of RHO, RAL, and RAC. The objective of this trial (NCT03900442) is to evaluate the safety, PK and PD of PTX-100 administered as monotherapy in patients with advanced malignancies, with an expansion cohort in T-cell lymphomas. PTX-100 was given by IV infusion in escalating doses of 500 to 2000 mg/m2 over days 1 to 5 in a 14-day cycle.
In order, to determine the optimal efficacious dose for PTX-100 and to further evaluate the clinical safety margin when administrated in multiple dose regime, a non-compartmental analysis (NCA) for PK and PD was performed, evaluating PTX-100 plasma pharmacokinetic parameters.
PTX-100 Tmax occurred in all patients within 1.3hr in each dose group. At Day1 and Day 5 of Cycle1, Plasma PTX-100 Cmax and AUC increased with increasing dose and appeared to be dose proportional over the range of 500 to 2000 mg/m2. Complete clearance of PTX-100 between doses/days has been found, with half-life of about 9hr.
To further evaluate and optimize PTX-100 dose regimens for Phase 2 efficacy, an exploration of efficacy correlation was investigated using a dose proportionality, modeling and simulation by Phoenix WinNonLin /NLME.
No PTX-100 accumulation was observed after five consecutive days of daily dosing. Simulation analysis revealed no correlation between total dose and time of response and neither between Cmax and time of response. Increase in total dose of PTX-100 dose levels beyond 2000mg/m2 correlates with decrease in overall response rate (ORR) and increasing PTX-100 dose does not reduce time to achieve ORR. However, it appears that 1500mg/m2 (i.e. total dose of 2500mg) is predicted to be the optimal dose achieving the optimum distribution of PTX-100 response.
In conclusion, PK and dose response analysis of Phase 1 study revealed that drug exposure is correlated with response to PTX-100. In contrast, no correlation is noted with dose or exposure, using hematology, RBC, WBC, Neutrophils, and Platelets. This evaluation provides information regarding the selection of the doses used in the clinic.