bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of Mortality of Pediatric Cancer Patients Admitted to the Intensive Care Unit (ICU) in a Low Middle Income Country (LMIC)
Authors: Helmy Rana , Khedr Reham , Madany Youssef , Kamal Mohamed , Mostafa Ali , Kieran Mark W. , Elhaddad Alaa M. 
Published: December 2024

BACKGROUND: Advances in cancer treatment have significantly improved survival rates for cancer patients, but this has also led to an increase in the number of pediatric cancer patients requiring ICU admission due to the severity of their illness and treatment complications. Understanding the predictors of mortality for this patient population is crucial for improving outcomes.
METHODS: A retrospective study including patients younger than or aged 18 years old at diagnosis of malignancy who were admitted to the medical ICU in The Children Cancer Hospital Egypt from January 1, 2019, to August 1, 2021. The primary objectives were to determine the mortality rate, identify the common causes of ICU admissions, and analyze the predictors of mortality among the pediatric cancer patients admitted to the ICU.
RESULTS: A total of 1,501 patients were included. The most common diagnoses were hematological malignancies, including acute lymphoblastic leukemia (24%) and acute myeloid leukemia (13%). The most common causes of admission were sepsis (39%) and respiratory failure (31%). 17% of patients were admitted to the ICU on presentation as new cases. The mortality rate for the whole cohort was 32%. The most common causes of death were sepsis (45%) and disease progression/relapse (28.6%). Multivariable analysis identified higher mortality for patients admitted with septic shock (OR= 6.01, 95%CI 3.97-9.23, P&lt;0.001) and respiratory failure (OR= 6.35, 95%CI 4.13-9.97, P&lt;0.001), patients with progressive disease (OR= 1.86, 95%CI 1.38-2.50, P&lt;0.001), those transferred from inpatient wards (OR= 1.63, 95%CI 1.20-2.22, P= 0.002) and patients with longer ICU stay (OR= 1.04, 95%CI 1.04-1.06, P&lt;0.001).
CONCLUSION: Pediatric cancer patients admitted to the ICU in LMICs have a high mortality rate, which confirms the need for targeted strategies to improve outcomes in this vulnerable population. Key approaches suggested by our research include early cancer diagnosis, optimized identification of early warning signs of critical illness, and decreasing sepsis-related mortalities by strict infection control, early diagnosis, and antimicrobial stewardship programs.
KEYWORDS: pediatric oncology, ICU admissions, mortality predictors, respiratory failure, septic shock, LMICs, hematological malignancies, acute lymphoblastic leukemia
BGB-11417-203, an Ongoing, Phase 2 Study of Sonrotoclax (BGB-11417), a Next-Generation BCL2 Inhibitor, in Patients With Waldenström Macroglobulinemia
Authors: Lee Hui-Peng , Opat Stephen S. , Hrom John , Kliman David , Marlton Paula , Liu Peng , Du Chenmu , Lussier Amber , Zhang Jun , Guo Haiyi , Treon Steven P. 
Published: December 2024

Introduction: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that are refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM, but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM. Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy, and sonrotoclax in combination with zanubrutinib, in patients with WM has been initiated and is currently recruiting.
Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study among patients with histologically confirmed WM. Approximately 105 patients will be enrolled across 4 cohorts. Patients in Cohort 1 to 3 must have R/R disease with the following requirement: Cohort 1 enrolls patients R/R to both BTK inhibitor therapy and anti-CD20-based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI); Cohort 2 enrolls patients R/R to anti-CD20-based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy; Cohort 3 enrolls patients R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy. Patients in Cohorts 1 to 3 will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. Patients in Cohort 4 are previously untreated and will receive combination therapy with sonrotoclax plus zanubrutinib for up to 20 cycles. The primary endpoint of the study is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Secondary endpoints include MRR assessed by investigator (INV) in Cohorts 1 to 4, and by IRC in Cohorts 2 and 3; overall response rate and duration of response (INV, Cohorts 1 to 4; IRC, Cohorts 1 to 3); progression-free survival (IRC and INV, Cohorts 1 to 3); time to next treatment (INV, Cohort 4); overall survival (Cohorts 1 to 3); and safety and tolerability. Patient recruitment is ongoing, with approximately 72 study sites in Australia, China, Europe (Italy, Spain, France, Greece), the UK, Canada, and the US.
Real-World Retrospective Analysis of Immune Thrombocytopenia Patient Demographics and Treatment
Authors: Lee Sophia , Sherry Emily Grace , Auster Michael , Benkhadra Raed , Pandya Abhishek , Ocampo Miguel , Karnad Anand , Bowhay-Carnes Elizabeth 
Published: December 2024

Background
Immune thrombocytopenia (ITP) is a serious immune-mediated phenomenon with an increasing incidence of 6.1 per 100,000 people. This incidence almost doubles in older adults 65 years or older, with an increased mortality risk found in fatal bleeding. Several treatment options are available, including corticosteroids, rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RA), immunosuppressives, and spleen tyrosine kinase inhibitors.
Aims
This retrospective study aims to investigate the ITP demographics and the preferred treatment modalities in a dataset from real-life clinic practice.
Methods
We conducted a retrospective chart review of adult patients diagnosed with ITP and treated in eit her inpatient or outpatient between January 2020 to January 2023. Data variables were collected and reviewed in descriptive analysis.
Results
Our study included 109 patients with ITP diagnosis. The most common ethnicity was White or Caucasian (52 patients, 48%) and Hispanic or Latino (42 patients, 39%). Many patients had primary ITP (82 patients, 75%), while 25% (27 patients) had secondary ITP with the most had concurrent active autoimmune disease (11 patients, 42%). 60% treated outpatient and 40% inpatient. At the time of diagnosis, 27 (25%) patients had bleeding episodes; and major bleeding occurred only in 4 (4%) patients. Initial treatments were steroid monotherapy (43 patients, 39.4%), observation only in 31 (28%) patients, and steroid and IVIG combination in 24 (22%) patients. Subsequently, 55 (50%) patients experienced refractory or relapsed disease, with Rituximab (17 patients, 31%) as the most common second-line treatment. The most common third-line treatment was Romiplostim (7 patients, 23%) and Rituximab (7 patients, 23%), whereas the fourth-line treatment was Eltrombopag (7 patients, 32%).
Conclusion(s)
This retrospective study provides the largest ITP analysis to our knowledge. Further research, including survival analysis, is needed to optimize the sequencing of subsequent ITP treatments and enhance patient outcomes in this challenging disease phenomenon.
Autosomal Recessive COPZ1 Mutations Cause Isolated Severe Neutropenia or Complex Syndrome with Severe Neutropenia
Authors: Borbaran Bravo Natalia Alejandra , Deordieva Ekaterina , Doll Larissa , Elgamacy Mohammad , Dannenmann Benjamin , Azevedo Joana , Iannuzzo Alberto , Delafontaine Selket , Lehners Moritz , Kolodziej Marius , Hernandez Alvarez Birte , Hellmuth Anna-Sophia , Ritter Malte Ulrich , Findik Betül , Zakharova Viktoria , Bräuning Sandro , Kandabarau Sergey , Lengerke Claudia , Feil Robert , Meyts Isabelle , Delon Jerome , Templin Markus , Sturm Marc , Rieß Olaf , Zeidler Cornelia , Welte Karl , Shcherbina Anna , Klimiankou Maksim , Skokowa Julia 
Published: December 2024

We have identified new autosomal recessive mutations in the COPZ1 gene in three severe congenital neutropenia (CN) patients from two unrelated families. In one family, two siblings with a stop-codon COPZ1 mutation (NP_057141:p.Gln141Ter) suffered from CN, lymphopenia, anemia, thrombocytopenia, and syndromic organ involvement, including hepatosplenomegaly, atypical autism with mental retardation, varying degrees of bone defects, and dermatitis. An unrelated patient with a missense COPZ1 mutation (NP_057141:p.Gly132Arg) exhibited isolated CN and chilblains.
The COPZ1 gene encodes the zeta 1 subunit of the coatomer protein complex I (COPI), which is phylogenetically highly conserved, with two identified mutation positions in the conserved region. The protein structure of human COPZ1 is still unknown, and computational analysis using bovine COPZ1 and COPG1 proteins predicted that truncated COPZ1 exhibits substantial structural instability and reduced interaction with COPG1, whereas missense COPZ1 retains interaction with COPG1. Consistent with structural defects, truncated COPZ1 blocked retrograde protein transport from the Golgi to the ER in human fibroblasts, suggesting a detrimental effect on COPI complex functions.
We also found that truncated or missense COPZ1 mutations caused impaired granulocytic differentiation of human CD34+ cells in vitro with a more pronounced phenotype in COPZ1 truncated cells. In zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated COPZ1 downregulated JAK-STAT-C/EBPE-G-CSFR signaling and hypoxia-responsive pathways while inducing interferon-stimulated genes (ISGs) and STING, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species (ROS) levels in CD34+ cells. Missense COPZ1 protein also deregulated interferon signaling.
Therapeutically, by applying connectivity map analysis, we discovered that treatment with the HIF1α activator IOX2 successfully restored granulopoiesis in truncated Copz1 zebrafish embryos and human CD34+ cells. Furthermore, transduction with COPZ2 cDNA effectively corrected granulocytic differentiation defects in COPZ1-mutated CD34+ cells.
In summary, our findings elucidate the distinct pathogenic mechanisms and clinical presentations associated with truncated versus missense COPZ1 mutations and underscore the potential of HIF1α activation as a promising therapeutic approach for CN.
Safety and Efficacy of Corvalimab in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Single-Arm Meta-Analysis
Authors: Patel Zeel V , Saddique Muhammad Nabeel , Patel Shivani , Javaid Hammad , Gummalla Vaishnavi , Desai Bhavya Yauvanbhai , Bethineedi Deepak Lakshmi , Patel Kush Pareshkumar , Prajjwal Priyadarshi , Asfeen Ummul 
Published: December 2024

Title: Safety And Efficacy of Crovalimab in Paroxysmal Nocturnal
Hemoglobinuria (PNH): A Systematic Review and Single-arm Meta-analysis
Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is rare, genetic, life-threatening
haematological disease affecting 12-13 individuals per 1 million worldwide, caused by mutation
in PIGA gene. PNH is associated intravascular haemolysis, thrombosis and pancytopenia with up
to 35% 5-year mortality rates. Crovalimab, a novel FDA-approved C5 inhibitor, appeared to
promising therapy for C5 mutation patients with less effective outcomes on conventional
therapies.
Objective: To evaluate the safety and efficacy of Crovalimab in paroxysmal nocturnal
hemoglobinuria (PNH).
Methods: The PubMed, Embase, Scopus and Cochrane databases were systematically searched
using relevant keywords from inception until July 2024. A total of 3 studies fulfilling predefined
selection criteria were included. We performed meta-analysis of prevalence using MetaXL
Software (version 5.3). We pooled the prevalence rate presented as untransformed proportion
with the corresponding 95% confidence interval (CI) using the random effects model. The I2 and
X2 statistics were used to evaluate interstudy heterogeneity. A heterogeneity of I2 &gt; 50% was
considered significant.
Results: We found the pooled prevalence of ≥1 any-grade adverse event (AE) of any cause 92%
(95% CI 0.76-1.00,I2=85%) and serious adverse event of any cause 15% (95% CI 0.05-0.29,
I2=75%). We found the pooled prevalence of ≥1 treatment-related any-grade AE 47% (95% CI
0.20-0.75, I2=91%) and serious AE 3% (95% CI 0.01-0.06, I2=0%).The pooled prevalence of the
patients with hemolysis control was 79% (95% CI 0.73-0.84, I2=0%), post-baseline transfusion
avoidance 59% (95% CI 0.50-0.68, I2=19%), stabilized hemoglobin 59% (95% CI 0.46-0.71,
I2=59%) and breakthrough hemoglobin 9% (95% CI 0.06-0.13, I2=0%)
Conclusion: We found that crovalimab showed less prevalence of both any-cause and treatment-
related adverse events, a high proportion of patients with controlled hemolysis, post-baselines
transfusion avoidance and stabilized hemoglobin in patients with PNH. Moreover, only a small
proportion of patients had breakthrough hemoglobin. More robust studies with larger sample
sizes are required to establish conclusive evidence.
Novel Fusion Gene PTPRC-Cyrib As a Drug Resistance Mechanism in T-ALL
Authors: Li Xindi , Yin Le , Wang Zhihua , Sheng Yue , Cheng Zhao , Peng Hongling 
Published: December 2024

OBJECTIVE
To investigate the mechanisms of resistance conferred by the novel fusion gene PTPRC-CYRIB in T-cell acute lymphoblastic leukemia (T-ALL).

METHODS
Using next generation sequencing, we identified the novel fusion gene PTPRC-CYRIB in the bone marrow of a primary drug-resistant T-ALL patient, subsequently confirmed its presence by Sanger sequencing. Molecular cloning techniques were employed to construct a plasmid overexpressing the PTPRC-CYRIB gene. Stable overexpression of PTPRC-CYRIB in T-ALL cell lines was achieved via lentiviral transduction. The T-ALL cell line overexpressing PTPRC-CYRIB was designated as the overexpression (OE) group, while the control group (NC) consisted of cells transduced with empty vector. Polymerase chain reaction (PCR) and western blotting (WB) confirmed PTPRC-CYRIB gene expression in transduced cells. Growth curves were plotted to assess proliferation rates, colony formation assays were conducted to evaluate clonogenic potential, and cell counting Kit-8 (CCK8) assays were performed following treatment with Vincristine, Idarubicin, Cyclophosphamide, and Prednisone to determine drug resistance in the OE group compared to the NC group.

RESULTS
We successfully constructed stable T-ALL cell lines overexpressing PTPRC-CYRIB. PCR and WB analysis confirmed PTPRC-CYRIB overexpression in the OE group compared to the NC group. Growth curve analysis revealed significantly increased proliferation rates in the OE group. Colony formation assays demonstrated enhanced clonogenic potential in OE cells. Following drug intervention, CCK8 assays indicated significantly reduced inhibitory effects of Vincristine, Idarubicin, Cyclophosphamide, and Prednisone on proliferation in the OE group compared to the NC group, with statistical significance (P &lt; 0.05).

CONCLUSION
Overexpression of the fusion gene PTPRC-CYRIB in T-ALL may contribute to the development of drug resistance.
Tucidinostat Plus Pediatric-Inspired Chemotherapy As First-Line Therapy for Newly Diagnosed ETP-ALL/Lbl: An Open-Label, Single-Arm, Phase 2 Trial
Authors: Lin Jieping , Ding Chenhao , Huang Zicong , Zihong Cai , Li Jia , Wang Zhixiang , Li Xiaofang , Zhou Xuan , He Bailin , Zhong Wenhao , Xuan Li , Liu Qifa , Xu Yang , Zhou Hongsheng 
Published: December 2024

Background Early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is a distinct subtype of T-ALL/LBL, with a dismal prognosis. The aim of this study was to investigate the effectiveness and safety of histone deacetylase inhibitor (HDACi) tucidinostat combined with pediatric-inspired chemotherapy for new diagnosed ETP-ALL/LBL.
MethodsThis phase 2 trial was conducted at Nanfang Hospital in China. Patients aged 14-55 years with newly diagnosed ETP-ALL/LBL were eligible. Patients received pediatric-inspired chemotherapy in combination with tucidinostat, which was orally administered once daily at a dosage of 10 mg from induction therapy to consolidation therapy. The primary endpoint was 3-year event-free survival (EFS). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), complete remission rate and adverse events. This study is registered with ClinicalTrials.gov, number NCT03553238.
Findings From June 2018 to June 2022, 54 patients with ETP-ALL/LBL were enrolled (37 [68%] male; 17 [32%] female; 54 [100%] Asian; median age 24 years [IQR 19-31]). The composite complete remission (CRc, complete response [CR] plus complete response with incomplete blood count recovery [CRi]) rate and MRD negativity after induction therapy was 91% (49 of 54 patients) and 65% (35 of 54 patients), respectively. The MRD negativity after consolidation was achieved in 87% patients (47 of 54 patients). With a median follow-up of 39.3 months (IQR, 20.6 to 60.0), the 3-year EFS rate was 67.7% (95% CI 56.2-81.7), the 3-year OS rate was 71.5% (95% CI 60.2-84.9) and the 3-year RFS rate was 67.5% (95% CI 55.9-81.6). The most common grade 3-4 adverse events were neutropenia (94%), anemia (85%), thrombocytopenia (76%), infection (53%), and hypokalemia (21%).
InterpretationTucidinostat plus pediatric regimen is an effective and well-tolerated regimen for new diagnosed ETP-ALL/LBL, with high CRc and MRD negativity rates, as well as encouraging survival outcomes.
GATA1 Insufficiencies in Dysmegakaryopoiesis of Myelodysplastic Syndromes/Neoplasms
Authors: Li Fuhui , Zhang Yudi , Li Chengwen , Sun Qi , Liu Jinqin , Qin Tiejun , Xu Zefeng , Li Bing , Qu Shiqiang , Pan Lijuan , Gao Qingyan , Jiao Meng , Gale Robert Peter , Xiao Zhijian 
Published: December 2024

Introduction: GATA1 is one of critical transcription factors for megakaryopoiesis and platelet production. Our study aimed to explore the correlations between GATA1 expression and dysmegakaryopoiesis in myelodysplastic syndromes/neoplasm (MDS).
Methods: Data of blood cell counts, cytogenetics and next-generation sequencing from 90 MDS patients at diagnosis were collected. Firstly, we assessed GATA1 expression level of megakaryocytes by performing immunohistochemical staining on bone marrow biopsy sections from the aforementioned 90 MDS patients. According to GATA1 expression level of megakaryocytes and positive megakaryocyte percentage, we assigned each patient a GATA1 score. Furthermore, we explored the correlation between GATA1 expression levels and cytogenetic abnormalities of the same megakaryocytes using the morphology antibody chromosome (MAC) technique on fresh bone marrow smears from another 6 MDS patients. To explore the significance of GATA1 expression levels in the prognosis of MDS, we included GATA1 scores in a multivariable analysis of overall survival (OS).
Results: Patients with abnormal karyotypes showed decreased GATA1 scores than those with normal karyotypes (6.0 [3.0-10.5] versus 12.0 [4.0-12.0] scores, P = 0.024). Compared with TP53-wildtype patients, GATA1 scores significantly decreased in TP53-mutated patients (3.0 [2.3-6.0] versus 12.0 [6.5-12.0] scores, P &lt; 0.001). However, patients with mutations of other genes showed no significant differences in GATA1 scores compared with wildtype patients (P &gt; 0.05). GATA1 expression levels were significantly downregulated in dysplastic megakaryocytes, especially micromegakaryocytes (P &lt; 0.001). Furthermore, we found that GATA1-negative megakaryocytes had higher frequencies of cytogenetic abnormalities (87.5% versus 47.6%, P = 0.002) using MAC technique. The multivariable analysis of overall survival that lower GATA1 scores (P = 0.005) were significantly associated with inferior OS in MDS, independent of the IPSS-R higher-risk category (IPSS-R scores &gt; 3.5 points).
Conclusion: Our results indicated that decreased GATA1 expression level of megakaryocytes was significantly associated with TP53 mutations, abnormal karyotypes and dysmegakaryopoiesis in MDS, suggesting that downregulation of GATA1 expression levels of megakaryocytes plays a critical role in the pathogenesis of MDS.
Clinical Response and Safety for Relapsed/Refractory Diffuse Large B Cell Lymphoma Treated By Glofitamab Combined with Chemo-Free Regimens
Authors: Zhao Xia , Liu Zhihe , Xu Junqing 
Published: December 2024

Background:
The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) is poor. Glofitamab, a bispecific antibody that recruits T cells to tumor cells, has shown promise. Still, real-world data on its combined use with chemo-free regimens for R/R DLBCL is limited.
Aims:
This study aimed to evaluate the clinical efficacy and safety of glofitamab combined with chemo-free regimens for treating R/R DLBCL.
Methods:
We enrolled patients with R/R DLBCL who had received at least two prior lines of therapy. Patients were pretreated with obinutuzumab to mitigate cytokine release syndrome, followed by fixed-duration glofitamab monotherapy (12 cycles). R/R double-expressor lymphoma patients received glofitamab combined with acalabrutinib (100 mg twice daily) or zanubrutinib (160 mg twice daily); R/R primary mediastinal large B-cell lymphoma patients received glofitamab combined with sintilimab (200 mg per cycle); the remaining R/R patients received glofitamab combined with polatuzumab vedotin (1.8 mg/kg) or lenalidomide (20 mg/day, days 1-14). Clinical information, overall response rates, and adverse events were collected for all patients.
Results:
Fifteen R/R DLBCL patients, with a median age of 66 years (range 29-79 years), were enrolled. The male-to-female ratio was 12:3. Based on the Ann Arbor staging system, 93.3% of patients were classified as stage III/IV, and 66.7% had an International Prognostic Index (IPI) score of ≥3. 66.7% of patients had at least two extranodal lesions. According to the Hans algorithm, 93.3% of patients were in the non-GCB group, and the median Ki-67 value was 90% (range 70%-90%). Three patients were CD5 positive, and 60.0% were diagnosed with double-expressor lymphoma. Among the cohort, three patients had P53 protein expression less than 5%, while eight patients exhibited expression greater than 50%. The median number of treatment lines was four (range 3-5). Six patients had primary refractory disease, and six experienced early relapsed. In this study, nine patients received glofitamab combined with BTK inhibitors; one received glofitamab combined with sintilimab; three received glofitamab combined with lenalidomide; and two received glofitamab combined with polatuzumab vedotin. All patients completed at least three cycles, and the overall response rate was 73.3%, with a complete response rate of 33.3% at the end of the second cycle. Adverse events were generally mild, with grade 1 or 2 cytokine release syndrome and tumor flare reaction being the most common.
Conclusion:
Glofitamab combined with chemo-free regimens demonstrated high response rates and good tolerability in R/R DLBCL patients receiving at least two-line treatments.