bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient Characteristics and Treatment Outcomes of TP53 Mutated Myeloid Neoplasms : A Single Cancer Center Experience from the MENA Region
Authors: Al-Rabi Kamal , Ma'Koseh Mohammad , Al-Batsh Tamer , Al Sawalha Karim , Zayed Anas , Yaseen Abeer , Ahmad Yazan Talab , Halahleh Khalid , Da'Na Waleed Kamel , Marei Lina , Barakat Farid , Alsmadi Osama , Abdel Rahman Zaid , Shahin Omar Ahmad , Abdel-Razeq Hikmat 
Published: December 2024

Background and objectives: TP53 mutations occur in about 10% of myeloid malignancies and are linked to poor prognosis despite intensive treatments. This study aims to improve treatment outcomes by gaining a better understanding of the clinical features, cytogenetic profiles, molecular characteristics, and outcomes of TP53-mutated myeloid neoplasms.
Methods: Next Generation Sequencing (NGS) database at King Hussein Cancer Center was used to identify adult patients (≥ 18 years) with TP53 mutated myeloid neoplasms, diagnosed and treated at KHCC between 2014 and 2023. Baseline characteristics are summarized using descriptive statistics. The Kaplan-Meier method was used to compare overall survival between different cytogenetic and treatment groups.
Results: During the study period, 55 patients with TP53-mutated myeloid neoplasms were enrolled. Median age was 57 (22-84) years, and 35 (64%) were males. Myeloid neoplasms include AML (n=26, 47.2%), MDS (n=24, 43.6%), and MPN (5, 9.1%). Prior malignancies were present in 14 (25.5%) patients, and 12 (21.8%) had therapy-related neoplasms. Cytogenetic studies showed that 26 (55.3%) patients had complex karyotypes. The most common TP53 mutation was the missense mutation, found in 43 (78.2%) patients. Intensive chemotherapy was administered to 21 (38.2%) patients, while 19 (34.5%) received low-intensity regimens. Allogeneic stem cell transplantation (AlloSCT) was performed on 21 (38.2%) patients. After a median follow-up of 11 months, the median overall survival (OS) for the entire cohort was 9 months (95% CI, 6.8-11.2). Survival was worse in patients with complex karyotypes; 5 months (95% CI 1.3-8.7), compared to 12 months (95% CI, 8.2-15.9, p=0.005) in patients with other cytogenetics. There was no significant difference in survival between intensive and low-intensity therapy groups. However, AlloSCT improved OS rates in the entire cohort (12 months, 95% CI, 9.5-4.5 vs. 4.0 months, 95% CI, 0.0-9.71, p=0.006) and among those who received intensive chemotherapy (12 months, 95% CI, 10.3- 13.7 vs. 7 months, 95% CI, 0.0-14.9,p=0.007).
Conclusions: In this limited sample of patients with myeloid neoplasms, the presence of complex karyotype, in addition to TP53 mutation, is associated with poorer prognosis. AlloSCT can improve survival, but overall outcomes remain dismal compared to other genetic groups.
Establishing a Patient-Derived Immortalized Erythroid Progenitor Cell Model to Investigate Disease Mechanisms and Lentiviral Gene Therapy Vector in Congenital Dyserythropoietic Anemia Type II
Authors: Taak Ravina , Babu Dinesh , Jamwal Manu , Palani Dhavapriya , Sharma Prashant , Bhatia Prateek , Bansal Deepak , Velayudhan Shaji R , Das Reena 
Published: December 2024

Congenital dyserythropoietic anemias (CDAs) are rare inherited disorders characterized by ineffective erythropoiesis. Type II CDA (CDA II) is the most prevalent, caused by mutations in the SEC23B gene. Clinically, CDA II is manifest by mild to severe anemia, relative reticulocytopenia, jaundice, hepatosplenomegaly, and cholelithiasis. Bone marrow erythroblasts in these patients show erythroid hyperplasia and 10-30% binucleation or occasionally multinucleation. Previous in-vivo models using mice and zebrafish have not accurately replicated the disease phenotypes observed in humans.
In this study, we aimed to establish a patient-derived immortalized erythroid progenitor cell (iEPC) model to investigate disease mechanisms. We isolated peripheral blood mononuclear cells (PBMNCs) from two patients with clinical and pathological phenotypes consistent with CDA II, both of whom exhibited SEC23B mutations as identified by next-generation sequencing. One patient, compound heterozygous for mutations NM_006363.4:c.1043A&gt;G and NM_006363.4:c.1898delC, displayed more severe symptoms and was transfusion-dependent, unlike the other patient, who was compound heterozygous for mutations NM_006363.4:c.1589G&gt;A, and NM_006363.4:c.1905+3G&gt;T and did not require transfusions.
Using a lentiviral vector, we transduced the PBMNCs with HPV E6/E7 genes and cultured them in erythroid progenitor expansion medium, successfully generating immortalized erythroid progenitors that were maintained for over 90 days. These iEPCs expressed erythroid markers CD71 and CD235a and were predominantly in the proerythroblast or basophilic erythroblast stages. The iEPCs could be differentiated into later stages of erythropoiesis using a cytokine-enriched medium. Despite typical expression kinetics of CD71, CD105, and CD235a during differentiation, the CDA II iEPCs showed reduced enucleation compared to a wild-type iEPC line, indicative of ineffective erythropoiesis.
Morphological analysis using Giemsa stain revealed binucleation in 20 to 30% of cells at the orthochromatic stage. Transmission electron microscopy showed a discontinuous double membrane in mature erythroblasts of both CDA lines. Western blot analysis confirmed reduced SEC23B expression in the CDA II lines. RNA sequencing of iEPCs pre- and post-differentiation identified novel pathways involved in disease pathogenesis. After transducing the iEPCs with a lentiviral vector expressing SEC23B, we observed a significant decrease in binucleated cells and an increase in terminally differentiated cells.
Our results demonstrate that iEPCs can be successfully generated from patients with rare red cell diseases and that CDA II disease modeling using iEPCs is viable for studying disease mechanisms and evaluating gene therapy vectors.
Treatment Outcomes for Patients with
TP53
-Mutated Mantle Cell Lymphoma: A Systematic Review and Meta-Analysis
Authors: Zhang Na , Xu Jiegang , Luo Chengxin , Zeng Dongfeng , Xu Shuangnian , Li Xi 
Published: December 2024

Abstract
Background TP53 mutation, which is present in 10% to 20% of patients with mantle cell lymphoma (MCL), is the most poor predictor of early disease progression and death for MCL patients. Many clinical trials have been conducted to improve the therapeutic efficacy for these patients, but the best available treatment is still unknown. Thus, we conducted a systematic review and meta-analysis to evaluate the outcome of current various treatments for TP53-mutated (TP53m) MCL.
Methods EMBASE and MEDLINE were searched from inception to December 29, 2023 without language restriction. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies which reported the treatment outcomes for newly diagnosed or relapsed/refractory TP53m MCL patients were included. Outcomes included complete remission (CR) rate, overall response (OR) rate and overall survival (OS).
Results A total of 28 studies which met the inclusion criteria were included in this systematic review and meta-analysis. The treatment approaches for TP53m MCL patients in the included studies contained targeted therapy, targeted therapy combined chemotherapy, hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T-cell (CAR-T) therapy. The CR rate and OR rate for TP53m MCL patients with the current treatment was 68% (95%CI 57%-79%, I2=41%) and 79% (95%CI 65%-90%, I2=71%) respectively. For newly diagnosed TP53m MCL patients, targeted therapy was reported to be with the highest CR rate of 79% (95%CI 62%-93%, I2=3%) and the highest OR rate of 96% (95%CI 82%-100%, I2=10%). For relapsed/refractory TP53m patients, CAR-T therapy showed the highest CR rate of 84% (95%CI 64%-98%, I2=43%) and the highest OR rate of 95% (95%CI 73%-100%, I2=62%). The 1-year OS rate and 2-year OS rate for TP53m MCL patients with the current treatment was 63% (95%CI 52%-73%, I2=20%) and 53% (95%CI 38%-69%, I2=44%) respectively. For newly diagnosed TP53m MCL patients, 1-year OS rate and 2-year OS rate for allo-HSCT was 69% (95%CI 50%-83%, I2=54%) and 62% (95%CI 45%-77%, I2=0%), respectively. For relapsed/refractory TP53m MCL patients, 1-year OS rate was 43% (95%CI 10%-82%) for targeted therapy, 61% (95%CI 47%-73%) for CAR-T therapy, and 2-year OS rate was 44% (95%CI 32%-58%) for CAR-T therapy.
Conclusions Although targeted therapy or CAR-T therapy can achieve an relatively high response rate for newly diagnosed or relapsed/refractory TP53m MCL patients, survival was still poor for these patients and more effective treatment strategies need to be exploded.
Flavopiridol Restores Granulopoiesis in an Experimental Model of Severe Congenital Neutropenia
Authors: Dannenmann Benjamin , Nasri Masoud , Doll Larissa , Findik Betül , Bernhard Franka , Kandabarau Sergey , Klimiankou Maksim , Lengerke Claudia , Zeidler Cornelia , Welte Karl , Skokowa Julia 
Published: December 2024

Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways that cause maturation arrest of granulocytic progenitors. The largest group of CN patients harbors autosomal dominant ELANE mutations (ELANE-CN).
We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of ELANE-CN and identified signaling pathways deregulated by ELANE mutations in iPSC-derived hematopoietic stem and progenitor cells, potentially leading to defective granulopoiesis. We further performed an in silico drug repurposing analysis of the transcriptomics data and selected flavopiridol, an FDA-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic.
We found that treatment with low-dose flavopiridol (up to 10-fold lower than that usually used to treat cancer patients) rescued defective granulopoiesis in primary CD34+ cells of CN patients with different inherited gene mutations, including ELANE, HAX1, SRP54 and JAGN1, in vitro and in two zebrafish CN models in vivo (hax1-CN and jagn1b-CN) without any toxic effects on hematopoietic stem cells or granulocytes and leading to fully functional granulocytes.
We have previously shown that the expression levels of the transcription factor CEBPA are severely reduced in hematopoietic cells and myeloid progenitors of CN patients. Rescue of defective granulopoiesis by transduction of CD34+ cells from CN patients with CEBPA further supports its key role in the pathogenesis of CN. CEBPA is known to counteract CDK2 and CDK4 activity to induce granulopoiesis and we found that flavopiridol restored granulopoiesis caused by reduced CEBPA expression in vitro and in zebrafish embryos in vivo. These data provide insight into the mechanism of action of flavopiridol in rescuing defective granulopoiesis in CN.
Thus, we described for the first time a therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.
SMARCC1 Controls the Oncogenic NOTCH1 Transcriptional Program in T-Cell Acute Lymphoblastic Leukemia
Authors: Shoumariyeh Khalid , Sun Xiaoyang , Poggio Teresa , Andrieux Geoffroy , Schmitz Tatjan , de Bra Stephan , Fotouhi Omid , Nizamuddin Sheikh , Martens Uta Sabine Sabine , Duyster Justus , Timmers Marc , Boerries Melanie , Miething Cornelius 
Published: December 2024

Introduction: Mutations in NOTCH1 are highly prevalent in T-ALL and aberrant NOTCH1 signaling is required for maintenance of the leukemogenic state in T-cell progenitors. However, little is known about which interaction partners are functionally required for oncogenic NOTCH1 signaling. We therefore aimed to identify previously unappreciated molecular dependencies required for NOTCH1-driven T-ALL cells.
Methods: We performed an in vitro miR-E-based loss-of-function RNAi screen employing an shRNA-library targeting 340 genes of the NOTCH1-interactome in a murine model of human intracellular NOTCH1 (hICN1)-induced T-ALL (Tx17 cell line). To identify NOTCH1-specific depletors, the screen was also performed in two murine Notch1-negative cell lines, the pro-B-cell line BaF/3 and the T-cell lymphoma cell line EL4.
Results: We identified Smarcc1 as the top NOTCH1-specific candidate in our screen. Smarcc1 knockdown in Tx17 cells resulted in rapid depletion of shRNA-expressing cells and induction of apoptosis.These results were confirmed in the NOTCH1-dependent human T-ALL cell line JURKAT and by probing public data from the depmap portal, revealing a strong SMARCC1-dependency in the two most NOTCH1-dependent cell lines tested, JURKAT and PF-382. Pulldown of human SMARCC1 in Tx17 cells and proteomic analysis revealed binding of all known SWI/SNF complex members and Notch1. Retransplantation of Tx17 cells harboring Smarcc1 or neutral shRNAs and in vivo shRNA induction led to a significantly decreased spleen infiltration of Tx17 cells transduced with the Smarcc1 shRNA compared to a neutral shRNA. RNAseq analysis of Smarcc1 depleted cells indicated a differentiation switch from DP to CD4 SP cells, implicating Smarcc1 as a mediator of NOTCH1-induced differentiation blockade.
Conclusion: By functionally interrogating the molecular networks directly involved in NOTCH1 signaling in a murine model of hICN1-induced T-ALL, we identified Smarcc1 as a major contributor to oncogenic NOTCH1 signaling. Knockdown of Smarcc1 in NOTCH1-driven T-ALL cell lines resulted in apoptosis and rapid depletion of shRNA-expressing cells. Mechanistically, Smarcc1 binds NOTCH1 and regulates a NOTCH1-dependent transcriptional program. In ongoing investigations including CUT&RUN analysis, we are currently further probing the precise mechanism through which Smarcc1 maintains aberrant NOTCH1 signaling in T-ALL.
Radiopsy, Quantitative Wb-Mri Adc and Fat Fraction Sequences for Discrimination of Smoldering Multiple Myeloma and Multiple Myeloma: A Prospective Observational Study
Authors: Cerchione Claudio , Rossi Alice , Caroli Paola , Marchesini Matteo , Matteucci Federica , Cangini Delia , Barone Domenico , Nappi Davide , Bezzi Davide , Sarnelli Anna , Martinelli Giovanni , Normanno Nicola , Feliciani Giacomo 
Published: December 2024

Purpose: To distinguish between Multiple Myeloma and High-Risk Smouldering Myeloma at staging using image-based biomarkers obtained from Whole Body-MRI (WB-MRI) Apparent Diffusion Coefficient (ADC) and Fat Fraction (FF) sequences.
Methods and Materials: From January 2021 to March 2024, we enrolled consecutive myeloma patients at staging into an observational prospective trial and divided them into two groups based on International Myeloma Working Group (IMWG) criteria: High-risk Smouldering Multiple Myeloma (SMM, group 1) and Multiple Myeloma (MM, group 2). All patients underwent WB-MRI using the Myeloma Response Assessment and Diagnosis System (MY-RADS). We use the term “Radiopsy” to indicate the quantification and modelling of image characteristics nearby the biopsy site to predict patient status. An experienced radiologist placed a cylindrical, 5 cc VOI nearby the biopsy site and 5 more identical VOIs on distant sites such the pelvis bone and on D11 and L5 vertebrae. The dataset was split into a training and test set with a 70:30 ratio. LASSO algorithm was used to select the most predictive features and build logistic regression models, which were then validated using the test set. Receiver operating curves (ROC) and area under the curve (AUC) were used as metrics for models' performance assessment. Radiopsy models were tested on distant biopsy site to predict disease invasion.
Results: The study included 102 patients (46 males, mean age 63 ± 12 [SD]) with 60 diagnosed with MM and 42 with SMM. 144 quantitative features were extracted from the VOI at the biopsy site WB-MRI ADC and FF sequences for each patient. Radiopsy model showed a median AUC of 0.85 (0.79-0.95) in the training phase and a median AUC of 0.65 (0.55-0.80) in the test phase. The best predictive model had an AUC of 0.95 and 0.75 in the training and test phase, respectively. The models used to predict patient status at biopsy site were also predictive in distant VOIs.
Conclusions: Radiopsy models can distinguish between MM and SMM with good performance nearby the biopsy site. Radiopsy can be used to predict disease invasion on distant sites where biopsy is not possible or not feasable
Clinical Relevance/Application: This observational prospective trial showed that using quantitative features extracted from WB-MRI ADC and FF sequences can help distinguish between high-risk SMM and MM at staging, thus potentially enhancing diagnostic accuracy.
Metabolic Tumor Volume after Two Cycles of Chemotherapy in Patients Treated for Advanced-Stage Hodgkin Lymphoma: Analysis of the German Hodgkin Study Group Phase III HD18 and HD21 Trials
Authors: Ferdinandus Justin , Kaul Helen , Schneider Gundolf , Fuchs Michael , Eich Hans Theodor , Baues Christian , Rosenbrock Johannes , Roth Katrin S , Drzezga Alexander , Van Heek Lutz , Dietlein Markus , Borchmann Peter , Kobe Carsten 
Published: December 2024

Introduction:
PET-guided treatment is standard of care to treat patients diagnosed with advanced-stage classical Hodgkin Lymphoma (AS-cHL) in several countries. Here, we investigate the role of metabolic tumor volume (MTV) for the response assessment of patients treated for AS-cHL.
Methods:
The investigator-initiated phase III trials HD18 (NCT00515554) and HD21 (NCT02661503) randomized patients between 18-60 years with newly diagnosed AS-cHL to receive BEACOPP (HD21 standard arm, HD18) or BrECADD (HD21 experimental arm). All patients received two cycles of chemotherapy followed by response assessment after two cycles (PET-2). MTV after two cycles (MTV-2) encompassed all lymphoma tissue with standard uptake value &gt; 4. To exclude confounding of PET-guided treatment, we first analyzed MTV-2 in patients treated in control arms of HD18 who received 6 cycles of BEACOPP irrespective of PET-2 (C6-Cohort). Cox-regression models and Kaplan Meier estimates were used to analyze impact of MTV-2 on progression-free survival (PFS). Findings were validated in the full ITT cohorts of HD18 and HD21.
Results:
A total of 645 patients were included in the C6-Cohort, of these 471 (64.6%) were rated as DS1-3 in PET-2 and 569 (88.2%) had no residual MTV-2. Compared to patients with DS1-3 (5y-PFS 93.5%; CI95: 91.2-95.9), Patients with measurable MTV-2 had significantly inferior PFS (5y-PFS 77.5%; HR 3.62, CI95: 1.94-6.76), while patients without detectable MTV-2 and DS4 had similarly high PFS (5y-PFS 89.3%; HR 1.65; CI95: 0.8-3.38). In line with these results, in the analyzed ITT cohorts of HD18 (n = 1756) and HD21 (n= 1211), patients with DS4 but with completely resolved MTV-2 had similar outcomes as patients with DS1-3 (HD18: HR 1.12, CI95: 0.69-1.80; HD21: HR 1.03, CI95: 0.55-1.95), whereas patients with measurable MTV-2 featured higher risk of progression (HD18: HR 2.98, CI95: 1.92-4.64; HD21: HR 4.44, CI95: 2.78-7.09). Results were similar in both trial arms of HD21 (BEACOPP vs. BrECADD) and frequency of measurable MTV-2 was similar in HD18 post-amendment and HD21.
Conclusion:
Complete resolution of MTV after two cycles of first-line chemotherapy for AS-cHL occurs in a vast majority of patients and associates with favorable prognosis, irrespective of DS. Approximately 10% had measurable MTV-2 (i.e. any lesion with SUV &gt; 4) and face high risk of progression. Our results advocate implementation of quantitative biomarkers to refine response assessment in AS-cHL.
Inferior Survival of Chronic Phase Chronic Myeloid Leukemia Patients in Public Health System Compared to Social Security and Private Systems in Perú: A Real-Life Study
Authors: Pizarro-Perea Marlies , Samanez-Figari Cesar , Mallma Soto Victor Ivan , Arteta Cecilia , Diaz Bardales Carol , Calderon Hafid , Calle Cindy , Carbone Ethan , Castillo Claudia , López Córdova Naty , Huaman Veronica , Menacho Estefany , Molina Maribel , Sanchez Jorge , Seminario Victor E , Jiménez Tornero Gledy , Vargas Olga , Vera Maria Alejandra , Untama José L. 
Published: December 2024

Background: The prognosis and survival of Chronic myeloid leukemia (CML) patients have improved in the last decades. Peru is a developing country without a national register of Cancer, where CML patients are seen in three different healthcare systems with some disparities, the objective of this study is to compare the clinical characteristics of patients with CML at diagnosis and survival by healthcare system.
Methods: We performed a real-life observational retrospective study collecting epidemiological and clinical data of newly diagnosed CML patients from three different settings: public health (PH), social security (SS) and private (P). All the patients were treated according to the guidelines and resources of each center and the data was obtained from their respective database.
Results: We obtained data from 785 CML patients older than 14 years who were treated in three different healthcare systems since 2010: 297 patients at public health (PH), 424 at social security (SS) and 64 at private (P), respectively.
At the time of CML diagnosis, fewer patients were diagnosed in chronic phase (PC) at PH system (82.5%) compared to 95.4% and 95.3% at SS and P systems, respectively.
A total of 531 chronic phase (CP) patients had completed data and were evaluated. At Public system we found younger patients (mean age 41.3yo vs 47.9yo and 51yo for PH, SS and P), major M/F ratio (2.21 vs 1.65 and 1.13 for PH, SS and P), lower Hb levels (9.5 vs 10.17 and 11.3 g/dL for PH, SS and P systems), higher WBC (231 vs. 201 and 189 x 109/L for PH, SS and P).
About risk scores, fewer patients had high-risk Sokal score in P system (32.6%) in comparison with SS (54.8%) and PH (59.8%). In contrast, more pts had high-risk ELTS score in PH system (38.6%) compared to SS (23.6%) and P (18.4%).
Because of similarities we pooled the survival data of P and SS system and compared with PH, we found an inferior OS at PH compared to P and SS: 5y OS and 10y OS at PH was 81.5% and 72.1% in contrast to 91% and 81.9% for combined P and SS (Log-rank p 0,02).
Conclusion: The CML patients at public health system had more advanced phases of disease, were younger and had more adverse characteristics at diagnosis, and it correlates with inferior OS. This study could be used to promote national measures of public health to improve the outcome of CP CML patients in our country.