bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Amyloid-a (SAA) Is an Optimal Acute Phase Protein for Cytokine Release Syndrome in CAR-T Patients Exposed to Tocilizumab
Authors: Galli Eugenio , Pansini Ilaria , Corrente Alessandro , Baroni Silvia , Chiusolo Patrizia , Sica Simona , Sorà Federica 
Published: December 2024

Patients treated with CAR-T and experiencing cytokine release syndrome (CRS) are often exposed to tocilizumab (anti IL6R). After the administration, IL-6 peaks in serum determinations and looses its predictive power to associate with severity of CRS.
This study aimed to explore the role of Serum Amyloid A (SAA) as a potential biomarker for monitoring early toxicities, particularly in patients treated with CAR-T cells. The analysis included 34 consecutive patients treated with CAR-T therapy at our institution from May 2023 to June 2024. SAA levels were measured at multiple time points: before lymphodepletion, immediately before CAR-T infusion, and every other day up to day 14 post-infusion. Additional acute phase proteins (APPs), including C-reactive protein (CRP), interleukin-6 (IL6), interleukin-2 receptor (IL2R), procalcitonin, ferritin, soluble suppression of tumorigenicity 2 (SST-2), and soluble urokinase plasminogen activator receptor (SUPAR), were also assessed at these intervals.
The study found that median baseline SAA levels were elevated above the upper limit of normal and exhibited wave-shaped kinetics post-CAR-T infusion, peaking on day 4 and declining thereafter. SAA levels were significantly higher before lymphodepletion compared to day 14 levels. When comparing early responders to non-responders, non-responders showed higher median SAA levels before lymphodepletion and at the day 4 peak. SAA may therefore mark tumor-associated inflammation also in this context.
SAA levels were significantly higher in patients experiencing CRS of any grade, with a clear correlation between elevated SAA and CRS severity. However, no such correlation was found for immune effector cell-associated neurotoxicity syndrome (ICANS). Strong associations were also observed between SAA and other APPs, particularly CRP, procalcitonin, ferritin, SST2, and SUPAR, with moderate trends observed for IL6 and IL2R.
In a focused analysis on patients previously exposed to tocilizumab, SAA emerged as the best-performing APP in identifying patients at risk of clinically relevant (grade 2 or higher) CRS, with a ROC analysis yielding an AUC of 0.86, being superior to CRP, IL6. IL2R, procalcitonin, and ferritin. A cut-off of 70 mg/L for SAA was identified, offering a sensitivity of 87% and specificity of 83% in distinguishing patients with grade 2-4 CRS.
SAA is a valuable biomarker for assessing inflammation and CRS in CAR-T treated patients, particularly in those previously treated with tocilizumab, where traditional markers like IL6 may be less reliable. SAA measurement could guide clinical monitoring and intervention strategies, especially in settings where early detection of severe CRS is critical. Further research is recommended to confirm these findings and explore the broader applicability of SAA in CAR-T therapy.
Transcriptome Data Analysis of 80 B ALL Patients in China
Authors: Lin Yuehui , Liu Dan , Xia Yu , Xia Yu , Wu Tong , Zheng Qinlong 
Published: December 2024

Introduction: Recently, the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the 2022 International Consensus Classification (ICC) has proposed up to 26 genetically defined B cell acute lymphoblastic leukemia（B-ALL）entities and subtypes. However, several of them are hard to recognize with traditional diagnostic tests. Sequencing methods like whole genome sequencing or transcriptome analyses of B-ALL leukemia cells have been widely used in clinical studies and demonstrated effective tools that can provide comprehensive molecular profiling including driver genetic lessions as well as gene expression patterns.
Methods: Transcriptome sequencing analyses were performed for 80 retrospective B-ALL cases admitted to our medical team between October, 2020 and July, 2024. Among them, 79 were refractory or relapse（RR） even after hematopoietic stem cell transplantation（HSCT）, while only one was newly diagnosed. Testing specimens including bone marrows, blood or tissues with at least 5% leukemia cells. Oncogenic driver events of gene fusions, chromosome large scale copy number variation, and hotspot gene mutations were analyzed with an inhouse workflow. Subtypes were identified based on the gene expression profiles and characterized with those oncogenic mutations.
Results：All patients：37 females（F） and 43 males（M）, age from 2 to 70 years old.The genetic testing results show that: 15 pts were Unclassed（15/80，18.75%），M:F 7:8 with a median age of 22；7 pts were high hyperdiploid（7/80,8.75%）,M:F 4:3 with a median age of 5；3 pts were low hypodiploid（3/80,3.75%）：M:F 2:1 with a median age of 16；4 pts were KMT2A（4/80,5%）,M:F 1:3，with a median age of 53.5;9 pts were ZNF384（9/80,11.25%）,M:F 6:3, with a median age of 31；5 pts were MEF2D（5/80,6.25%）,M/F 0:5，with a median age of 30；9 pts were Ph positive（9/80,11.25%）,M:F 2:7 with a median age of 55；11 pts were Ph like（11/80,13.75%）,M:F 10:1 with a median age of 20；2 pts were ETV6-RUNX1（2/80，2.5%），M:F 1:1 with a median age of 15；7 pts were DUX4（7/80，8.75%）：F:M 2:5 with a median age of 18;2 pts were PAX5alt（2/80，2.5%）,M:F 2.0 with a median age of 26; 2 pts were PAX5 P80R（2/80，2.5%）,M:F 2.0 with a median age of 19.5; 3 pts were TCF3-PBX1（3/80，3.75%）,M:F 3.0 with a median age of 21;1pts was HLF,M,21.
Conclusions：
Our transcriptome sequencing indicate: only about 20% of B ALL pts belong to be unclassed, while remaining 80% of pts have clear molecular subtypes. This suggests that hematologists should try to perform whole genome sequencing or transcriptome analyses as much as possible when patients first diagnosis or relapse. This can help hematologists better understand diseases, also help patients achieve accurate diagnosis and obtain the best treatment. So far there are still many unknown molecular subtyping that need to be discovered and we still need further research in future.
The Efficacy and Safety of Huaiqihuang Granules in the Treatment of Childhood Chronic Primary Immune Thrombocytopenia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Clinical Study
Authors: Han Juan , Zhou Fen , Jin Runming , Shi Xiaodong , Li Jianxin , Fang Yongjun , Yuan Xiaojun , Luo Xuequn , Li Jianqin , Sun Lirong , Liu Wenjun , Yan Mei , Liu Yufeng , Liang Changda , Jiang Hua , Wu Runhui 
Published: December 2024

The efficacy and safety of Huaiqihuang Granules in the treatment of childhood chronic primary immune thrombocytopenia: a multicentre, randomized, double-blind, placebo-controlled clinical study
* Correspondence:
Fen Zhou, daisy_may@163.com
Runming Jin, jinrunm@qq.com
Abstract
Background: Chronic immune thrombocytopenia (CITP) is a hemorrhagic disease that seriously affects the quality of life of children and their families. Huaiqihuang Granules, a traditional Chinese medicine, has certain value in the treatment of ITP patients in the preliminary clinical findings. To investigate the efficacy and safety of Huaiqihuang Granules in children with CITP, we conducted a multicenter, randomized, double-blind, placebo-controlled study.
Methods: Patients with CITP were treated with Huaiqihuang Granules or with matching placebo in a randomized, double-blind, 24-week treatment period. Patients who received placebo and completed 24 weeks of treatment switched to receive Huaiqihuang Granules, and patients treated with Huaiqihuang Granules in the double-blind period continued Huaiqihuang Granules during the following open-label 24-week treatment.The patients were followed up for 96 weeks. Clinical effective (defined as those achieving a platelet count of≥30×109/L and at least twofold more than the basal platelet count, or the degree of bleeding decreased by one or more grade) was evaluated.
Results: Huaiqihuang Granules was superior to placebo in achieving a platelet response and in reducing the bleeding risk. The clinical effective rate of Huaiqihuang Granules group (71.74% in 24-week) was higher than that of the Placebo group (45.65% in 24-week, p=0.0013). The most common severe adverse events were respiratory tract infection (7.8%) and immune thrombocytopenic purpura (6.9%) .
Conclusions: In CITP children, Huaiqihuang granules can improve the clinical effectiveness especially the degree of bleeding, and shows good safety in long-term treatment.
Keywords: Chronic immune thrombocytopenia, Huaiqihuang Granules, efficacy; safety
Treatment of Chronic ITP with Avatrombopag: A Multicentric Real-World Experience
Authors: Troiano Mario , Giordano Claudia , Rossi Elena , Scalzulli Potito Rosario , Mettivier Laura , D'Ambrosio Alessandro , Mazzoni Daniele , Vatiero Erika , Selleri Carmine , Pane Fabrizio , Frigeri Ferdinando 
Published: December 2024

INTRODUCTION
Chronic immune thrombocytopenia (ITP) is a bleeding disorder characterized by a low platelet count that persists for 12 months or more. Initial treatments usually include corticosteroids or intravenous immunoglobulin (IVIG). For patients who are refractory or relapsed, or who may not adhere well to treatment, second-line therapies come into play. These include: i) Thrombopoietin receptor agonists (TPO-RAs) such as Romiplostim, Eltrombopag, or Avatrombopag, and ii) Rituximab or other immunosuppressive agents such as azathioprine, mycophenolate mofetil, or ciclosporin. Splenectomy, although an option, is generally considered a last resort for patients who do not respond to or tolerate other treatments.
AIM OF THE STUDY
To assess the efficacy and safety of Avatrombopag in patients with chronic ITP, stratified by prior exposure to other TPO-RAs.
RESULT
Fifty-seven patients with immune thrombocytopenia (ITP) treated with Avatrombopag were enrolled from five Italian hematology units. The median age at the start of treatment was 60.8 years (range 20.3 - 92.3), with a slight predominance of women (56.1%). Patients had received a mean of three prior therapies (range 0 - 10), and 43 patients (75.4%) had previously been exposed to at least one other thrombopoietin receptor agonist (TPO-RA).
At baseline, the median platelet count (evaluated in 54 patients) was 11000/mm3 (range 2000-50000). An additional 3 patients switched to Avatrombopag due to intolerance to other TPO-RAs, with no washout time, and had baseline platelet counts &gt; 90000/mm3.
The median time to platelet counts greater than 50000/mm3 (assessed from 54 patients who started with low counts) was 27 days (range 3 - 456 ). At a median follow-up of 4.9 months (range 0.3 - 14.6), 40 patients (70.2%) were still on treatment, with a median platelet count of 96000/mm3 (range 13000 - 403000). Thrombotic events were observed in 4 patients (7%), while bleeding events occurred in 5 patients (8.8%), but only 3 of these led to treatment discontinuation. Additionally, 4 deaths were recorded: 1 due to a COVID infection, 1 from acute renal failure, 1 from a subdural hematoma, and 1 unrelated death.
CONCLUSIONS
To our knowledge, this is the first large real-world experience reported in Italy for Avatrombopag treatment in patients with immune thrombocytopenia (ITP). Our data confirmed the high efficacy of this therapy, even in heavily pretreated patients, including those with prior exposure to one or two TPO-RAs. The safety profile was acceptable, with few adverse events (including thrombotic and hemorrhagic events) leading to discontinuation. However, more data and longer follow-up are needed to evaluate the duration of response.
Dynamic Changes in Peripheral Blood Lymphocyte Subset Counts and Functions in Children with B-Cell Acute Lymphoblastic Leukemia during and after Chemotherapy
Authors: Yin Tiantian , Han Juan , Qu Ping , Jin Runming , Zhou Fen 
Published: December 2024

Background: B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignant tumor in children. This study aimed to investigate the lymphocyte subsets, their activities and dynamic changes during and after chemotherapy in children wiht B-ALL.
Methods: Peripheral blood samples were prospectively and cross-sectional collected from B-ALL children at different treatment time points (50 cases at initial diagnosis, 40 cases after induction, 20 cases at the beginning of maintenance, 15 cases at 61 weeks, the middle of maintenance, 20 cases at the end of treatment, 18 cases at 5-year follow-up) and healthy control children. T, B and NK lymphocyte subsets, immunophenotypes and functions were detected by flow cytometry.
Results: Compared with healthy controls, T cells in patients newly diagnosed with B-ALL were in a state of inhibition, senescence and exhaustion. The percentages of CD4+, CD4/CD8, γδ T, CD4+Tnaive as well as CD8+Tnaive were significantly decreased (P &lt; 0.05). The percentages of CD8+, Tregs, CD4+Tcm, CD8+Tem, CD4+PD-1, CD4+TIM-3, CD8+PD-1 and CD8+TIM-3 were significantly increased (P &lt; 0.05). The levels of IFN-γ, IL-4 and IL-2 were significantly lower. NK and NKT cells in B-ALL children were in a state of inhibition, which mainly showed that the percentage of NK and NKT was significantly decreased, and the activator receptor NKP46 and NKG2D were significantly decreased (P &lt; 0.05). After induction therapy, the percentage of B cells decreased significantly (P=0.000), and T cells and NK cells had a partial recovery (P &lt; 0.05). When entering to maintenance therapy, T, B, NK cell percentage and T cell function of patients were the most severely impaired, and then gradually recovered. Till to the end of treatment, the function of lymphocytewas inhibited. At 5 years follow-up, the counts and functions of B and NK cells recovered, but that of T cells did not recover completely.
Conclusions: The absolute counts and functions of T cells and NK cells, which were significantly lower in children with B-ALL, gradually recovered after chemotherapy. Detecting the counts and functions of peripheral blood lymphocytes is important for identifying new prognostic markers of ALL, guiding to prevent infection and administering effective immunotherapy.
Visualization of Bortezomib Induced Peripheral Neuropathy By Dorsal Root Ganglion MRI in Patients with Multiple Myeloma
Authors: Zhou Xiang , Schindehuette Magnus , Cebulla Nadine , Öztürk Baran , Weiner Simon , Mersi Julia , Rasche Leo , Waldschmidt Johannes , Einsele Hermann , Blum Robert , Rittner Heike , Sommer Claudia , Pham Mirko , Kortüm Martin K. 
Published: December 2024

Background:
Whereas most treatments in multiple myeloma (MM) are stopped due to their inefficiency over time and the development of drug resistance, the use of the proteasome inhibitor bortezomib (BTZ) is mainly limited by its neurotoxic effects and the induction of BTZ induced neuropathy (BIPN). Of particular pathophysiological importance is the dorsal root ganglion (DRG), which plays a central role in the development of BIPN (Argyriou et al. Blood 2008). As early BIPN diagnosis and treatment adjustment is critical, we here investigated the predictive potential of DRG MRI and measured the DRG T2 signal intensity as a biomarker of inflammation in BTZ treated MM patients.
Methods: We recruited a total of 112 MM patients receiving BTZ either currently or in the past. Of these, 92 (82 %) had BIPN, which was painful in 37% (n=41) and mild and only detectable by sophisticated clinical-neurological diagnostics in 52% of patients (n = 58, severity Grade 1 with/without pain). DRG MRI was performed in a subset of 54 patients, including 45 of them with detectable BIPN (all grades), and additionally in 12 healthy controls. Using high-resolution three-dimensional T2-weighted fast spin-echo DRG MRI, we evaluated the lumbosacral DRG Th12-S2 bilaterally in all patients. Comparative analyses were performed using one-way ANOVA with Bonferroni correction. Pearson's Rho was used for the correlation analyses.
Results: Analysis revealed a significant increase in DRG T2 signal intensity in MM patients with BIPN compared to MM patients without BIPN (p= 0.005) and healthy controls (p= 0.003). Furthermore, an inverse correlation was found between DRG T2 signal intensity and intraepidermal nerve fiber density (IENFD) (p= 0.035). The mean DRG volume on L5+S1 level (in mm³) did not differ significantly between the groups, however, IENFD was significantly decreased in BIPN MM patients (n=26; 3.41 fibers/mm) compared to the healthy controls (n=12, 5.28 fibers/mm; p = 0.031), MM patients without BIPN showed no difference in IENFD (4.45 fibers/mm) compared to healthy controls.
Conclusion:
DRG T2 signal intensity is a surrogate marker of inflammation, and our observations suggest that inflammatory changes at the DRG level underlie BIPN in MM patients. Our imaging holds potential to be used as a non-invasive biomarker for early BIPN detection and to define patients at risk. This is an ongoing study, and imaging from the full cohort and from additional longitudinal assessment will be presented at the meeting.
Real World Outcomes of Ruxolitinib Treatment of Steroid Refractory/Dependent Acute Graft Versus Host Disease
Authors: Leung Becky , Butler Jason , Curley Cameron , Henden Andrea S , Hunt Stewart , Morton James , Subramoniapillai Elango , Stewart Caroline , Tey Siok-Keen , Kennedy Glen A , Scott Ashleigh P 
Published: December 2024

Aim:
Steroid-refractory and/or dependent acute graft versus host disease (SR/SD-aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT). The REACH-2 study established ruxolitinib as standard of care compared to historical salvage options, however patients with lower gastrointestinal (GI) involvement still have poor outcomes1. We aimed to review local outcomes of patients treated with ruxolitinib for SR/SD-aGVHD.
Method:
We performed a retrospective analysis of HSCT recipients treated between March 2021 and January 2024. The primary endpoint was overall survival (OS), with secondary endpoints including non-relapse mortality (NRM) and requirement for third line therapy.
Results:
We identified 37 patients with SR/SD-aGVHD, median age of 52 years at time of HSCT. All patients underwent T-replete HSCT using GCSF-stimulated PBSC. Donor source was matched sibling (27%), matched unrelated donor (49%), or haploidentical/mismatched (24%); with myeloablative conditioning in 35%. GVHD prophylaxis was cyclosporin/methotrexate (78%) or post-transplant cyclophosphamide/tacrolimus/mycophenolate (22%).
Acute GVHD occurred at median 41 days post-HSCT with grade III-IV disease in 48%, lower GI involvement in 68%, and skin-only disease in 27% at diagnosis. Following ruxolitinib commencement for SR/SD-aGVHD, the proportion of patients at D28/D56 with complete response was 62%/54% and overall response 78%/70%. Ruxolitinib failure occurred more frequently in patients with lower GI involvement compared to those without, with D28/D56 overall response of 69%/58% versus 100%/100%. Flares of aGVHD after initial response requiring third-line therapy occurred more frequent in patients with lower GI aGVHD (40% vs 0%).
At median follow-up of 159 days post ruxolitinib commencement, overall survival was 51% with mortality due to GVHD (56%), infection (22%) and relapse (6%). NRM occurred more frequently in patients with lower GI aGVHD (64% vs 8%).
Conclusion:
Our single-centre data supports ruxolitinib as second-line therapy for SR/SD-aGVHD. However, patients with lower GI involvement remain at significant risk for non-sustained response requiring third-line therapy and non-relapse mortality.
References: Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22. PMID: 32320566.
Multi-Cohort Meta-Analysis of Rnaseq Data to Determine Sex Bias in Pediatric Acute Myeloid Leukemia
Authors: Gardner Eve , Tokarski Ember , Jensen Ava , Harmon Lauren , Triche Timothy J 
Published: December 2024

Leukemia is the most common childhood cancer, and remains a leading cause of childhood cancer mortality. The most common leukemia in children, B-cell acute lymphoblastic leukemia, has a 92% cure rate (5-year overall survival). In contrast, pediatric acute myeloid leukemia (pAML) has a 68% cure rate, which has not changed significantly despite 40 years of trials.
AML exhibits some of the most striking sex-specific disparities in childhood cancer, affecting disease risk, therapy response, and transplant outcomes. pAML cohorts are consistently about 45% female and 55% male, yielding a male excess risk of 22%. Some aggressive subtypes, such as NUP98::NSD1 fusions seen in many treatment failures, the male:female ratio rises to 2:1, and to 3:1 near puberty. Up to 50% of pAML patients show loss of X or Y, with loss of Y (LOY) prognostic for lifetime all-cause mortality in males. Even mutation-targeted therapies such as midostaurin show significant differences in efficacy by sex in Phase III trials.
We sought to illuminate these differences via meta-analysis of bulk RNA sequencing (RNAseq) data from 2,000 TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative patients and matched controls to identify sex-specific transcriptional differences. Subsequently, we interrogated these findings by performing a meta-analysis and cross-projection of publicly available single-cell RNA sequencing (scRNAseq) data from a variety of pediatric hematopoietic malignancies from eight published GEO datasets and two Alex's Lemonade Stand Foundation (ALSF) datasets, comprising 225 myeloid or myeloid-like pediatric leukemia patients and 23 non-leukemic specimens. Using Non-negative Matrix Factorization (NMF), we projected all scRNAseq data into the same latent space as the Chan Zuckerberg Initiative (CZI) human, matched-tissue scRNAseq. These NMF projections were then utilized to inform a comprehensive meta-analysis of both bulk and scRNAseq data from myeloid-like diseases. By leveraging both bulk and single-cell transcriptomic data, we aimed to elucidate the role of sex in the molecular underpinnings of pediatric hematopoietic malignancies, potentially unveiling novel therapeutic targets and contributing to personalized medicine approaches in these diseases.
Combined with the development of new models for predisposition conditions such as RUNX1-FPDMM, our work begins to reveal the molecular underpinnings of sex bias in treatment response and immunogenicity for pAML patients, and creates a foundation to better understand how genetic lesions interact with age and sex to shape risk in this lethal malignancy.