bluuebunny/crossref_metadata_2025 huggingface dataset:
Intensive Chemotherapy Sequential with Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Refractory or Relapsed Acute Myeloid Leukemia: Case Series, Systematic Review and Meta-Analysis
Authors: Yan Jinsong , Hu Jiong , Zheng Jin , Liu Lusi , Li Chunhong
Published: December 2024

Background: One important therapeutic approach to refractory and relapsed acute myeloid leukemia (R/R AML) is allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients with R/R AML, however, the effectiveness of conventional conditioning regimens is limited. Of note, intensive chemotherapy sequential with a conditioning regimen has emerged as an effective treatment modality for leukemic cytoreduction in R/R AML. We retrieved relevant studies for systematic review and meta-analysis to understand the effects of intensive chemotherapy sequential with a conditioning regimen for R/R AML patients and reported a case series in our medical center to validate.

Methods: We searched literature from PubMed, Web of Science, EMBASE, the Cochrane Library, and ClinicalTrials.gov through July 2023 and collected 16 relevant cases in the single center to evaluate. We conducted all analyses using R software version 4.3.1. The pooled primary outcomes included the overall-survival (OS) rate and leukemia-free survival (LFS) rate of meta-analysis. The Kaplan-Meier method was used to calculate OS in the single center.

Results: The meta-analysis revealed a pooled 2-year OS rate of 38% (95% confidence interval [CI], 35-42%; I² = 57%, P = 0.01), a LFS rate of 34% (95% CI, 29-40%; I² = 73%; P < 0.01), and a 2-year non-relapse mortality (NRM) rate of 20% (95% CI, 17-23%; I² = 74%; P < 0.01). The 2-year OS rate in our case series was the same as that in our meta-analysis.

Conclusion: For R/R AML patients, intensive chemotherapy with sequential allo-HSCT demonstrated a promising trend toward a better OS and LFS, a reduced relapse rate, and a lower NRM. However, we need a prospective study with an even larger sample size to prove these findings.
Alpha-Enolase (ENO1) Promotes AML Progression Via the MAPK/ERK Pathway
Authors: Zhang Shanshan , Wang Haina , Yan Jinsong , Hu Jiong , Sun Mingzhong
Published: December 2024

Abstract：

Acute Myeloid Leukemia (AML) is a malignant clonal disease of the blood system, characterized by abnormal proliferation and impaired differentiation of myeloid cells, resulting in the accumulation of leukemia cells and abnormal hematopoietic function. Although targeted therapy has developed rapidly, drug resistance and relapse remain major challenges in AML treatment. Exploring the abnormal proteins driving leukemia development and searching for new therapeutic targets and drugs are key tasks for AML treatment.

Enolase-1 (ENO1) is a key enzyme in the glycolysis process, and its abnormal expression drives the development of various cancers. To clarify the role of ENO1 in the progression of AML, we studied the relationship between ENO1 and AML using database and patient transcriptome sequencing datafrom 185 AML patient samples. Our results confirm that ENO1 is highly expressed in AML patients and is associated with poor clinical outcomes. Knockdown of ENO1 in AML cells significantly inhibited their proliferation, cloning, migration, and invasion in vitro, blocked the cell cycle, and promoted apoptosis. We found that ENO1 was closely related to mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway through cell transcriptome sequencing data analysis. ERK pathway inhibitors significantly inhibited proliferation, clonal formation, migration, and invasion of AML cells in vitro, blocked cell cycle, and promoted apoptosis. And knockdown of ENO1 significantly inhibited ERK pathway proteins' phosphorylation. Most importantly, activators of ERK pathway could reverse the effects of ENO1 knockdown on AML cells. We also found that ENO1 knockdown inhibited the proliferation and invasion of AML cells in mice and significantly increase the overall survival rate of mice.

Altogether, these results not only reveal the role and mechanism of ENO1 in the development of AML but also highlight ENO1 as a potential therapeutic target in the treatment of AML.

Key words: AML, ENO1, Cell proliferation, Invasion
Huaier Inhibits the Stemness and Drug Resistance Via Regulating WNT/β-Catenin and YAP Signaling Pathways in IKZF1del-Ph+ALL
Authors: Huang Ziyi , Zhou Fen , Shang Mengxuan , Han Juan , Qu Ping , Shi Hui , Cheng Yiren
Published: December 2024

Background: With the development of TKIs, the prognosis of Ph+ALL has been significantly improved. However, Ph+ALL especially with IKZF1 deletion are more likely to relapse and drug resistance. Huaier is a tranditional Chinese medicine, which has been shown an effective adjuvant of cancer therapy. .Our study aims to explore the effect and mechanism of Huaier on the chemosensitivity of IKZF1del-Ph+-ALL.

Methods: Cell viability was analysed by CCK8 and High-throughput Drug Sensitivity Analysis Strategy. Flow cytometry was used to detect cell apoptosis, cell cycle and adhesion markers. RNAseq, RT-PCR and Western blot were conducted to discover the related gene and protein expresson of stemness pathway.

Results: Our studies demonstrated that Huaier enhanced the efficacy of chemotherapy. Using the concentration of GI25, GI50 and GI75 of Huaier combined with VDLP, dasatinib, mercaptopurine and methotrexate, it was found that Huaier could improve the cell inhibition rate of these chemotherapy drugs. Huaier combined with dasatinib could significantly increased the apoptosis of Sup-B15 cells (Control group vs. dasatinib group vs. Huaier group vs. Huaier + dasatinib group: 7.70%±0.67% vs. 58.70%±0.35% vs. 60.97%±0.55% vs. 73.17%±0.44%, p < 0.0001), arrested the cell cycle in the G0/G1 phase (Control group vs. dasatinib group vs. Huaier group vs. Huaier + dasatinib group: 46.70%±0.05% vs. 53.74%±0.82% vs. 58.63%±0.01% vs. 63.70%±0.69%, p < 0.0001) and reduced the expression of adhesion-related molecules, such as the mRNA expression of ITGA4, ITGA8, THY-1, ITGA9 (p < 0.0001), ITGA5 (p = 0.0231), and the protein expression of FAK (p < 0.0001) and phosphorylated FAK (p = 0.0026).

The result of RNAseq showed that the differentially expressed genes were enriched in stemness-related pathways, among which Wnt/β-catenin and YAP were significantly down-regulated. The mRNA expression of wnt3, wnt3a, DVL-3, c-myc, FZ2, TCF-1, c-jun and cyclinD1 was significantly decreased (P < 0.0001). Also, the WNT pathways downstream of the key moleculars protein expression of β-catenin, c-myc, c-jun, TCF1, TCF3, TCF4 (P < 0.01) and corresponding phosphorylated proteins (P < 0.05) were all decreased. Also the mRNA (P < 0.0001) and protein expression of YAP, CTGF and survivin were significantly decreased (P < 0.01) after Huaier treatment.

Conclusions: In our study, we proved that Huaier can inhibit the Wnt/β-catenin and YAP pathway to enhance the chemotherapy sensitivity of Ph+ALL.Therefore, Huaier has great potential for clinical application in the treatment of refractory/relapsed Ph+ALL.
Improving Resident Education & Comfort of Key Hematology, Oncology and Bone Marrow Transplant Topics
Authors: Aryee Emmanuel , Oduro Joana , LaCroix Megan , Graff Zachary
Published: December 2024

Background

Patients admitted to the Hematology, Oncology, and Transplant (HOT) unit often have specific needs and challenges which are often not encountered in other rotations. Unfamiliarity with the patient population and unit-specific knowledge and procedures have occasionally led to adverse outcomes as well as patient morbidity and mortality. Residents have reported knowledge gaps for HOT unit specific topics and expressed interest in both formal and informal didactic opportunities to improve patient care.

Objective

This is a quality improvement project designed to improve overall resident comfort levels in hematology, oncology and bone marrow transplant topics during residents' rotation in the HOT unit.

Design/Methods

We designed a “bingo” card of high yield topics that residents would likely encounter in the HOT unit. Paper copies were provided to residents in the beginning of their rotation. QR codes with copies of the “bingo” cards were also placed throughout the unit. Both resident and faculty were educated about the intervention and encouraged to utilize the cards during and after morning rounds. Whenever a topic was discussed, the corresponding box on the “bingo” card was marked as completed and signed by a faculty member. Residents turned in the “bingo” cards at the end of the rotation. A subsequent survey of resident perceived knowledge and comfort level with key topics and concepts on a 10-point Likert scale was conducted at the end of the rotation. We then conducted a pre-post analysis comparing resident knowledge of key topics before the rotation with their comfort and knowledge after the rotation. We additionally conducted a retrospective survey of resident who completed the rotation before the introduction of the “bingo” card to assess the utility of the intervention.

Results

Residents reported the greatest improvement in knowledge and management scores (5-6) on topics they were unlikely to encounter in other rotations such as Oncologic emergencies, Veno-occlusive disease (VOD) and Engraftment Syndrome as compared to cross-disciplinary topics like pain, nausea and decreased food intake (3-4). There were no differences found in the knowledge scores of residents who completed the rotation prior the introduction of the “bingo” card intervention. Residents who completed the rotation post intervention however reported finding the intervention helpful to their learning (80%).

Conclusion

Resident knowledge and comfort of key Hematology, Oncology and Bone Marrow Transplant topics improves after their rotation. This is particularly salient on topics that are not covered in other rotations. Introduction of a “bingo” card to promote learning was successful in engaging residents and helping them learn.
Clinical Characteristics and Prognostic Significance of PWWP2B Expression in AML Patients Treated with Intensive Chemotherapy
Authors: Chen Cheng-Yeh , Tsai Xavier Cheng-Hong , Sun Kuojui , Tien Feng-Ming , Kuo Yuan-Yeh , Tseng Mei-Hsuan , Peng Yen-Ling , Ko Bor-Sheng , Liu Ming-Chih , Liu Chia-Wen , Lin Chien-Chin , Yao Ming , Chou Wen-Chien , Tien Hwei-Fang , Hou Hsin-An
Published: December 2024

Background/Aim

PWWP domain containing 2b (PWWP2B) is a nuclear protein, which was reported to participate in the regulation of histone acetylation and chromatin modifying by forming complex with histone deacetylases (HDAC) proteins. HDACs are known to involve in chromatin remodeling. Abnormal HDACs functions may contribute to the leukemogenesis of acute myeloid leukemia (AML). Therefore, this study aimed to investigate the prognostic significance of PWWP2B expression in AML patients.

Methods

A total of 475 adult patients with newly diagnosed de novo non-M3 AML at the National Taiwan University Hospital, treated with intensive chemotherapy, were consecutively enrolled. PWWP2B expression level was detected by RNA sequencing assay. Maximally selected rank statistics were employed to find the optimal cutoff point for PWWP2B expression in survival analysis. Survival analyses were performed using the Kaplan-Meier model and the Cox proportional hazards model was used for multivariable analysis. Bioinformatics approaches for biological inference was conducted by Ingenuity Pathway Analysis.

Results

The ELN-2022 risk stratification of our AML patient cohort was as follows: 40.6% (n=193) classified as favorable, 28.2% (n=134) as intermediate, and 31.2% (n=148) as adverse. Higher PWWP2B expression was observed in AML patients compared to healthy donors (p<0.001). There is no significant difference in ELN-2022 risk stratification, age, initial leukocyte count, or gender between patients with higher and lower PWWP2B expression levels. Patients with higher PWWP2B expression had higher frequency of concurrent FLT3-ITD and SRSF2 mutation, but lower frequency of NRAS mutations. In terms of treatment outcome, AML patients with higher PWWP2B expression had a worse overall survival (OS) and relapse-free survival (RFS) compared to AML patient with lower expression (P <0.001 for OS and 0.003 for RFS). In multivariate analysis, higher PWWP2B expression level remained an independent adverse prognostic factor for both OS (HR 1.753, p<0.001) and RFS (HR 1.658, p=0.005) irrespective of age, ELN-2022, and leukocyte count at diagnosis. Intriguingly, allogeneic transplantation may overcome the poor prognosis associated with higher PWWP2B expression in AML.

Conclusions

We found that PWWP2B expression has prognostic significance in de novo AML patient treated with intensive chemotherapy. Higher PWWP2B expression is associated with worse survival outcomes. These findings suggest further investigation of HDAC targeted therapy in AML patient with high PWWP2B expression.
Clinical Significance of Genomic Landscape in Pediatric Advanced MDS
Authors: Liu Chenmeng , Wang Xingchen , Chen Yunlong , Wan Yang , An Wenbin , Ren Yuanyuan , Liu Fang , Guo Ye , Yang Wenyu , Zhu Xiaofan
Published: December 2024

Pediatric advanced myelodysplastic syndrome (MDS) is characterized by a dismal prognosis and a high frequency of mutations. In this study we aimed to assess the clinical significance of genomic landscape in pediatric advanced MDS. We performed next generation sequencing on the bone marrow sample of 72 children with diagnoses of advanced MDS, including RAEB(n=54) and RAEB-T(n=18), targeting genes closely associated with MDS or other hotspots from adult and pediatric myeloid neoplasms.

With only mutations with presumed functional consequences being considered, 83.3% of patients carried gene mutation. We found frequent mutations in PTPN11 (16 cases, 22.2%), SETBP1(14 cases, 19.4%), NRAS (12 cases, 16.7%), RUNX1(10 cases, 13.9%), NF1(9 cases, 12.5%), FLT3(8 cases, 11.1%), GATA2(8 cases, 11.1%), WT1(8 cases, 11.1%). PTPN11 was the most commonly mutated gene. In total, genes involved in the RAS/MAPK pathway, were the most common gene mutations（32 cases,44.4%). We found significant co-occurrence between PTPN11 and NF1 mutations (P=0.003), SETBP1 and EZH2 mutations (P=0.021), SETBP1 and GATA2 mutations (P=0.041), FLT3 and WT1 mutations (P=0.026). SETBP1 and GATA2 alterations were frequently detected in patients with monosomy 7(P<0.001). Children with mutations involved in the RAS-MAPK pathway displayed elevated blast percentages in both BM (14.25% VS 8%, P=0.018) and PB (4% VS 1%, P=0.024), and they also demonstrated a significantly higher likelihood of detecting splenomegaly (P = 0.007). A total of 63 children were available for follow-up. The median follow-up of the entire cohort of children was 27 months (range, 1-116 months). Although not statistically significant, alterations in PTPN11 appeared to be linked with an unstable disease progression. Children with PTPN11 mutations who did not undergo HSCT died within 3 to 18 months after diagnosis, except for one who was lost to follow-up three months post-diagnosis. In contrast, those who underwent HSCT achieved complete remission and remained alive at the last follow-up. Mutations in PTPN11 were significantly correlated with unfavorable EFS (HR:2.909, 95%CI: 1.303-6.495, P=0.009). Patients with mutated genes involved in the RAS/MAPK pathway exhibited similar event-free survival (EFS) and overall survival (OS) compared to those without such mutations. Overall, mutations in RAS/MAPK pathway are the most common genetic alterations in advanced pediatric MDS. PTPN11 alterations were associated with unfavorable EFS.
LDB1 Establishes Multi-Enhancer Networks to Regulate Erythroid Gene Expression
Authors: Aboreden Nicholas , Lam Jessica , Goel Viraat , Wang Siqing , Wang Xiaokang , Midla Susannah , Quijano Alma , Keller Cheryl A. , Giardine Belinda M. , Hardison Ross C. , Zhang Haoyue , Hansen Anders , Blobel Gerd A.
Published: December 2024

How specific enhancer-promoter pairing is established is still mostly unclear. While cohesin has been widely implicated in assisting CRE connectivity, it only influences a limited fraction of such contacts. Besides components of the CTCF/cohesin machinery, only a few nuclear factors have been studied via acute degradation to interrogate a direct/proximal role in physically connecting cis-regulatory elements (CRE). Here, we investigated the transcription co-factor LDB1 as a mediator of CRE connectivity. LDB1 is a widely expressed nuclear factor that is recruited to specific genomic sites by lineage specific transcription factors such as GATA1 and TAL1. Using an acute degradation system combined with Micro-C, we found that LDB1 directly and broadly promotes enhancer-promoter and enhancer-enhancer contacts to drive erythroid gene expression. To explore LDB1's interplay, if any, with cohesin, CTCF, and the transcription factor YY1 (which has been implicated in CRE interactions), we engineered acute degrons for all these factors. Notably, most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin or YY1. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1 occupied sites but aids in the formation of a subset of LDB1 dependent loops. Thus, structural loops and the process of cohesin-driven chromatin loop extrusion have a limited influence on regulatory connectivity established by LDB1. Leveraging the extensive and highly dynamic reorganization of nuclear architecture during the transition from mitosis to G1-phase, we defined the relationship between LDB1-dependent CRE interactions and contacts formed via cohesin-driven loop extrusion. During the mitosis-to-G1-phase transition, many LDB1 dependent CRE interactions formed prior to cohesin-driven contacts, demonstrating LDB1's ability to newly forge long range contacts independently of loop extrusion. Tri-C and ultra-high-resolution Region Capture Micro-C revealed that LDB1 organizes complex multi-enhancer networks to activate erythroid transcription. Lastly, super-resolution microscopy showed that LDB1 forms multi-molecular clusters which we speculate underly LDB1's ability to coordinate multi-enhancer interactions. Together, this work establishes LDB1 as a direct and potent driver of regulatory network inter-connectivity in erythroid cells and likely other lineages as well.
Zanubrutinib As Salvage Therapy for Refractory/Relapsed Hemophagocytic Lymphohistiocytosis in Adults: A Single Center, Prospective Study
Authors: Wang Jingshi , Song Deli , Wu Lin , Wei Na , Pi Yubo , Wang Zhao
Published: December 2024

Background：Uncontrolled immune activation and severe inflammation are the hallmarks of hemophagocytic lymphohistiocytosis (HLH) with no treatment response in approximately 30% of patients. With no established salvage treatment, ability of burton tyrosine kinase (BTK) inhibitors to resolve inflammations might be relevant treatment option for HLH. Here, we evaluated the efficacy and safety of zanubrutinib in patients with refractory/relapsed HLH.

Methods：In this single-center, single arm, prospective trial, HLH patients were treated with 160 mg zanubrutinib twice daily for 8 weeks. Efficacy in terms of overall response (OR), complete response (CR) and partial response (PR) at 2, 4, 6, and 8 weeks along with safety was assessed.

Results: A total of 16 patients were enrolled who had a median age of 33.5 years (range 19-74 years) and most patients had connective tissue diseases (n=9; 56.3%). Overall response (OR) after 2 weeks of treatment was 86.7% among with 1 (6.7%) and 12 (80%) patients achieved CR and PR respectively. After 8 weeks, 8 patients were excluded due to various clinical reasons and all the remaining 8 patients achieved CR. Among the 9 patients with macrophage activation syndrome (MAS), 5 (62.5%) achieved CR at 8 weeks. Proinflammatory cytokines, IL-1, IL-10, and IFN-γ significantly decreased (P<0.05) 2 weeks post-zanubrutinib. Fatigue, ecchymosis, and nausea were the most common adverse events and 1 patient died due to cerebral infarction combined with cerebral hemorrhage.

Conclusions: Zanubrutininb showed promising efficacy making it an effective candidate for HLH salvage therapy. However, further confirmations with large-scale studies would be welcoming.
Myeloma-Associated Macrophages Protect Tumor Cells By Reprogramming of Lipid Metabolism through SREBP1
Authors: Guo Xing , Dai Zhenfeng , Zhang Enfan , Cai Zhen
Published: December 2024

Introduction: With the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has significantly improved. However,MM remains incurable due to drug resistance. Hence, there is an urgent need to develop novel therapeutic targets and agents. Lipid metabolism disorder is one of the important characteristics of drug-resistant myeloma cells. While statins can induce drug resistance by regulating lipid metabolism in MM and can also increase MM cells' sensitivity to chemotherapy, the key factors in MM cells' lipid metabolism remain u unrevealed. Myeloma-associated macrophages (mMΦs) are prominent components in the bone marrow of MM patients and induce drug resistance by protecting tumor cells from chemotherapy-induced apoptosis. However, no studies have investigated whether mMΦs regulate lipid metabolism of myeloma cells. Therefore, our study aims to explore the role of mMΦs in MM lipid metabolism, and further understand the molecular mechanisms involved.

Results: Our study found that the fatty acid (FA) in MM cells increased significantly after cocultured with mMφs detected by flow cytometry, and FA could protect MM cells from apoptosis induced by bortezomib, which suggested that mMφs could probably induce MM drug resistance through lipid metabolism regulation. To explore the molecular mechanisms in the process, RNA sequencing was used to detect the differential genes expression involved in lipid metabolism cocultured with or without mMφs. We further found that expression of SREBP1, a key transcription factor of FA synthesis increased significantly in MM cells after cocultured with mMφs. And the result was validated by qPCR and western blot. Importantly, we found that SREBP1 in CD138+ plasma cells of relapsed myeloma patients was significantly higher than that of newly diagnosed patients by double immunofluorescence techniques.

Conclusion: Our study found that mMφs may promote FA synthesis in MM cells through regulating SREBP1, and ultimately induce MM drug resistance, which suggested that lipid metabolism pathway is a possible target for MM treatment.
Dilute Russell's Viper Venom Time Correction Ratio and Thrombosis: A Single Centre Retrospective Cohort Study
Authors: Chao David , Tian Ke , Kwok Andrew John , Chan Natalie PH , Wong Raymond SM
Published: December 2024

Background: Antiphospholipid syndrome (APS) is a thrombo-inflammatory disorder associated with significant morbidity and mortality. In the diagnosis of APS, lupus anticoagulant (LA) testing plays a crucial role. This testing involves assessing the presence of LA using a correction ratio calculated from the dilute Russell's Viper venom Time (dRVVT), a functional assay. Additionally, other antiphospholipid antibodies, such as anti-cardiolipin and anti-beta-2 glycoprotein I, have demonstrated a positive correlation between their titers and thrombotic events.

Aim: This study aims to evaluate the hypothesis that the correction ratio derived from dRVVT can predict the risk of thrombosis in patients who have tested positive for LA on more than one occasion.

Patients and methods: We conducted a single center retrospective cohort study, focusing on patients who are repeatedly tested positive for LA between September 2020 and June 2023. A total of 167 patients were included in the analysis. The mean age of the cohort was 50.4 years (±16.8), with 43.7% male and 56.3% female. We calculated both the highest and mean dRVVT correction ratios. Logistic regression was employed, with thrombosis as the dependent variable. Additionally, we performed a receiver operating characteristic (ROC) analysis to assess the predictive quality of the proposed model. Finally, we stratified the population into quartiles to illustrate the escalating risk of thrombosis at higher correction ratio quartiles.

Results: Among the 167 patients, 63 (37.7%) developed thrombosis. After adjusting for confounding factors, the odds ratio for thrombosis occurrence is 40.9 (95% CI [10.6-157.7], p < 0.01) per 1-unit increase in the highest dRVVT correction time. Similarly, the odds ratio for thrombosis occurrence is 72.2 (95% CI [14.2-367.8], p < 0.01) per 1-unit increase in the mean correction ratio. Additionally, a Pearson's correlation test revealed that the highest dRVVT correlates with activated partial thromboplastin time (APTT). Using the same logistic regression model, the odds ratio for thrombosis occurrence is 1.052 (95% CI [1.023-1.081], p < 0.01) per 1-unit increase in APTT when adjusted for covariates. Furthermore, ROC-AUC analysis demonstrated an area under the curve (AUC) of 0.805 (95% CI [0.735-0.874]). Quartile analysis revealed that the odds ratio for developing thrombosis in the 4th quartile, compared to the 1st quartile, is 30.5 (95% CI [9.8-113.9], p < 0.01).

Conclusion: The correction ratio derived from the dRVVT test positively correlates with thrombotic events. Our data suggest that dRVVT should be further studied as a predictive model for thrombosis.
An Anti-Apoptotic Protein C17ORF58 Is Critical for the Maintenance of Human Peripheral T-Cell Lymphomas By Suppressing BBC3-Induced Apoptosis
Authors: Tobon Julian , Opavska Jana , Libby Kaitlynn , Abdelghany Reem , Veizaj David , Sabripour Bayan , Shaw Jaclyn , Thompson Candalyn , Opavsky Rene
Published: December 2024

Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of T- and NK-cell malignancies characterized by diverse cells of origin, varied cytogenetic, molecular, and morphological phenotypes, and antigen variability. They account for approximately 15% of non-Hodgkin lymphomas. Despite treatments with conventional chemotherapy like CHOP and R-CHOP, as well as targeted therapies such as belinostat, romidepsin, pralatrexate, and brentuximab vedotin, the overall 5-year survival rate remains low at 20-30%. Thus, improving PTCL therapies necessitates the identification of novel targets crucial for lymphoma cell survival.

C17ORF58 is an uncharacterized human gene that encodes several isoforms with molecular weights of 37 kDa, 11 kDa, and 9 kDa. The longest isoform encodes a protein with a predicted consensus disordered region and signal peptide in the N-terminal region, as well as a Netrin-like domain in the C-terminal region. Such structural features are found in complement proteins and various proteases, but its function remains unclear. C17ORF58 is overexpressed in the vast majority of human PTCL subtypes, including Anaplastic Large Cell Lymphoma, Angioimmunoblastic Lymphoma, and PTCL-Not Otherwise Specified (PTCL-NOS). The mouse homolog of C17ORF58, 1810010H24Rik, is highly expressed in various normal tissues, including the lungs, heart, kidneys, and skeletal muscle, but at low levels in the brain. In hematopoietic organs, 1810010H24Rik protein expression varies, with low levels in the bone marrow and medium levels in the thymus and spleen, potentially indicating a role in blood cell maturation. Interestingly, the protein is up-regulated in mouse T-cell lymphoma induced by the loss of DNA methyltransferase 3a, suggesting that, as in humans, increased expression is closely linked to PTCL development.

The downregulation of C17ORF58 does not affect the proliferation of normal primary human T-cells or the human embryonic kidney cell line HEK293T. In contrast, the loss of C17ORF58 function in T-cell lymphoma and leukemia lines T8ML-1 and Jurkat inhibits proliferation by inducing G2-M arrest and apoptosis. Loss of C17ORF58 leads to the upregulation of numerous signaling pathways, including p53 and MAPK signaling, apoptosis, angiogenesis, and hypoxia. Consistently, C17ORF58 knockdown in T-cell lines results in the upregulation of numerous pro-apoptotic genes, including BBC3 (PUMA), EPAS1, ATF5, DUSP8, S100A6, and CHAC1. Importantly, shRNA-mediated knockdown of BBC3 suppresses apoptosis induced by C17ORF58 loss of function, suggesting that BBC3 is a key downstream target negatively regulated by C17ORF58.

Altogether, our data suggest that C17ORF58 is an anti-apoptotic protein exerting its activity by suppressing BBC3-induced apoptosis, presenting a potential novel target for improving PTCL therapies.
Elts Score Is an Effective Tool to Predict Leukemia-Related Mortality in Peruvian Patients with Chronic Myeloid Leukemia
Authors: López Córdova Naty , Mallma Soto Victor Ivan , Samanez-Figari Cesar , Pizarro-Perea Marlies , Arteta Cecilia , Calderon Hafid , Calle Cindy , Carbone Ethan , Castillo Claudia , Diaz Bardales Carol , Huaman Veronica , Jimenez Tornero Gledy , Molina Maribel , Sanchez Jorge , Seminario Victor E , Vargas Olga , Vera Maria Alejandra , Untama José L.
Published: December 2024

Introduction:

The ELTS (EUTOS-long-term survival) score was developed to predict the probability of leukemia-related mortality in patients with chronic myeloid leukemia (CML) diagnosed in the chronic phase (CP). In Perú, there is a lack of registries that reflect the mortality associated with leukemia in CML patients.

Objectives:

This study aims to evaluate the impact of the ELTS score and the SOKAL score to estimate leukemia-related mortality in a cohort of patients from 6 hospitals in Lima-Perú.

Methodology:

A real-life observational retrospective study collected epidemiological and clinical data of de novo CML patients diagnosed between 2007 and 2024, from 6 hemato-oncology centers in Lima. Patients were treated according to each center's guidelines and resources, and the data was obtained from their respective databases.

Results:

In 507 CP-CML patients (ratio male/female 1.77) with a median age of 45.48 years old (7 - 90 yo), the Sokal score was low in 19.9% (n= 101), intermediate in 25.6% (n=130), and high in 54.4% (n=276). ELTS score was low in 37.1% (n=188), intermediate in 33.5% (n=170), and high in 29.4% (n=149) of patients.

There was a total of 85 deaths in all the cohort, of which 53 were leukemia-related, 29 were non-leukemia-related and 3 were from unknown causes. According to the ELTS score, there were 22 (14.8%), 16 (9.4%), and 15 (8%) leukemia-related deaths in the group of high, intermediate, and low risk, respectively. With the Sokal score, the leukemia-related deaths were 32 (11.6%), 7 (5.4%), and 14 (13.9%) in the group of high, intermediate, and low risk, respectively.

The cumulative incidence of leukemia-related mortality according to the ELTS score at 5 and 10 years was: 17.5% and 32.3% (high risk), 9.1% and 23.6% (intermediate risk), 5.39% and 14.1% (low risk) respectively (p=0.013). According to the Sokal score, we did not find a statistically significant difference in leukemia-related mortality in the different groups.

Conclusions:

In this Peruvian cohort, we found that the ELTS score was an effective tool for estimating the risk of leukemia-related mortality, in contrast to the Sokal score. To our knowledge, this is one of the first studies in Latin America about the impact of ELTS score in CML patients.
Non-Canonical Genetics of Hereditary Spherocytosis: A Clinical Case Report
Authors: Banks Alexander S , Flier Sarah N , Heeney Matthew M.
Published: December 2024

A 7-year old male with Duane Retraction Syndrome and ADHD exhibited progressive lethargy, jaundice, and splenomegaly following multiple bouts upper respiratory infection symptoms. Lethargy persisted despite the resolution of URI, lethargy persisted. He had long-standing anemia (Hb 9-10g/dL), reticulocytosis (ARC 0.4-0.5 M cells/uL), elevated MCHC (34-36 g/dL) and spherocytes on blood smear lead to a clinical diagnosis of hereditary spherocytosis (HS). There is no family history of HS or other hemolytic anemias. Osmotic fragility was slightly increased and erythrocyte Band 3 expression by flow cytometry was reduced.

Although the clinical severity of HS is highly variable, patients typically present with hemolytic anemia and progressive splenomegaly at a frequency of 1:1000-2000 in the population. Loss-of-function mutations within 5 genes (ANK1, EPB42, SLC4A1, SPTB, and SPTA1) cause defects in cytoskeletal structure. The result is increased cell fragility and decreased cellular half-life due to weakened linkage of the erythrocyte plasma membrane to the cytoskeleton. Genetic testing of a limited panel of anemia-associated genes revealed only a heterozygous variant of unknown significance, EPB42 (chr15-43220725-C-T/ rs150530456/c.100+1G>A) affecting splicing of the minor transcript EPB42-206. In contrast, patients with complete loss of function of EPB42 exhibit autosomal recessive HS Type 5. We performed whole genome sequencing to identify other genetic changes that could contribute to the onset HS. Our patient has low polygenic risk scores for variants affect surrogate markers of HS-associated traits including changes in reticulocyte count and mean corpuscular hemoglobin concentration (MCHC). Finally, we nominate rare variants as potentially pathogenic based on the following criteria: low observed frequency in the population, the predicted effect of the variant on protein function, high levels of protein expression in mature erythrocytes, and the observed consequence of these variations on hematological parameters in the UK Biobank population. In the absence of a single, large-effect mutation, we propose an oligogenic composite of factors producing a mild clinical case of hereditary spherocytosis.
Cytogenetic Risk Stratification in a Centre Colombian Multiple Myeloma Patients
Authors: Sandoval-Sus Jose , Sossa Claudia , Salazar Luis Antonio , Peña-Castellanos Angela , Rosales Acevedo Manuel Leonidas , Orozco Oviedo Carlos Alberto , Perez Carlos Andres , Morales Chacon Katherinee , Luna-Gonzalez Maria , Prada-Sepúlveda Ana María , Alvarez Juliana , Tarazona-Bohórquez Melanie , Ochoa Miguel
Published: December 2024

Introduction:

Multiple myeloma (MM) is a heterogeneous disease with patient outcomes influenced by guest factors, clinical presentation, and genetic abnormalities. This study aimed to classify MM patients into risk groups based on cytogenetic markers and assess their impact on survival.

Methods:

We conducted a prospective cross-sectional study involving 50 MM patients (aged >18 years) treated at Clinica Foscal between October 1, 2021, and July 31, 2023. Patients with smoldering MM were excluded. Genetic studies (FISH, molecular studies, and karyotyping) were performed.

Results:

The cohort consisted of 52% men with a median age of 67 years (range: 46-91). Most patients were urban residents (86%) with health insurance coverage (62%). The most common MM subtype was IgG kappa (38%), followed by IgG lambda (18%) and IgA kappa (12%). Cytogenetic abnormalities included del13q (32.5%), amp1q21 (20%), t(4;14) (15%), and t(11;14) (12%). Abnormal karyotypes were observed in 69% of patients.

Using the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) scale, 46% of patients were classified as high risk, while 18% were categorized as standard risk. According to the Revised International Staging System (R-ISS), 14% were classified as stage I, 56% as stage II, and 18% as stage III. Among those with abnormal karyotypes, 27.6% were high-risk by mSMART, and 58.6% were stage II by R-ISS.

First-line chemotherapy included Lenalidomide-Bortezomib-Dexamethasone (VRD) in 54.5% of patients, Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) in 27.3%, Daratumumab plus VRD in 2.3%, and other regimens in 15.9%. No patient achieved complete remission before 4 cycles. Due to the sample size and limited follow-up, the impact of risk stratification on treatment response could not be fully assessed.

Regarding overall survival (OS), at the time of analysis, only the R-ISS showed a statistically significant difference in OS, favoring patients classified as stage I.

Conclusion:

Cytogenetic markers are crucial prognostic factors in MM. In this study, only the R-ISS scale demonstrated utility in refining risk stratification within the follow-up period. Extended follow-up is necessary to establish the prognostic value of other risk stratification scales and to evaluate their potential role in guiding first-line treatment decisions.
Results of Protocol of Treatment-Free Remission in a Small Cohort of Patients with Chronic Myeloid Leukemia in a Essalud Hospital, Lima - Peru
Authors: Pizarro-Perea Marlies , Untama José L. , Navarro-Cabrera Juan Ramon
Published: December 2024

INTRODUCTION

Chronic Myeloid Leukemia is a disease whose prognosis and survival have significantly improved since the beginning of the use of tirosinkinase inhibitors (TKI). Achieving a sustained deep molecular response has lead to start succesful treatment suspension programs in other settings and stablished guidelines and recommendatios to carry out this suspension of TKI. The object of this work is to present a Real World data in a hospital in a developing country with limited resources. This kind of programs allow us to improved quality of life of patients, however, is mandatory a close follow up specially at the beginning to asses if a restart treatment is needed.

METHODS

An observational, descriptive and retrospective study was performed collecting data from patients with Chronic Myeloid Leukemia (CML) registered at the data base of our institution.

RESULTS

At our hospital, from a cohort of 398 patients with diagnosis of CML between 1996 and 2024 registered in the data base, we performed a count of whom treatment was suspended. A total of 17 patients between 2016 and 2024 were found, 13 of them with medical indication for suspension of treatment, and 4 by own decision. At the time of discontinuation, the supervised group had an average disease duration of 7.04 years [4.89 - 11.83], while the other group had 8.16 years [3.78 - 10.49]. The following results were obtained: Of the 13 patients in protocol, 69.2% (9 patients) remained under observation without loss of molecular response. Of the 4 patients without treatment by their own decision, only 25% (1) remained under observation.

Besides, the average time to restart treatment due to loss of molecular response in the protocol group was 4.81 months [2.73 - 7 months), while for the unauthorized group it was 11.8 months [5.6 - 16.4 months]. At the time of completing the registry, the average treatment-free remission (TFR) time for the within-protocol group was 26.9 months, and 96 months for the only patient in the opposite group.

CONCLUSION

At our hospital, patients with Chronic Myeloid Leukemia who initiated treatment discontinuation within a protocol are a small population yet, although, doing so in a supervised setting generates better opportunities to maintained without therapy by a better selection of suitable patients. Furthermore, the results of this study allow us to keep this measure which is really usefull especially in countries with limited resources for diseases requiring long term therapies.
Detecting departures from the conditional independence assumption in diagnostic latent class models: a simulation study
Authors: Okkaoglu Yasin , Welton Nicky J. , Jones Hayley E.
Published: December 2024

Background

Latent class models can be used to estimate diagnostic accuracy without a gold standard test. Early studies often assumed independence between tests given the true disease state, however this can lead to biased estimates when there are inter-test dependencies. Residual correlation plots and chi-squared statistics have been commonly utilized to assess the validity of the conditional independence assumption and, when it does not hold, identify which test pairs are conditionally dependent. We aimed to assess the performance of these tools with a simulation study covering a wide range of scenarios.

Methods

We generated data sets from a model with four tests and a dependence between tests 1 and 2 within the diseased group. We varied sample size, prevalence, covariance, sensitivity and specificity, with 504 combinations of these in total, and 1000 data sets for each combination. We fitted the conditional independence model in a Bayesian framework, and reported absolute bias, coverage, and how often the residual correlation plots, $${G}^{2}$$

G

2

and $${\chi }^{2}$$

χ

2

statistics indicated lack-of-fit globally or for each test pair.

Results

Across all settings, residual correlation plots, pairwise $${G}^{2}$$

G

2

and $${\chi }^{2}$$

χ

2

detected the correct correlated pair of tests only 12.1%, 10.3%, and 10.3% of the time, respectively, but incorrectly suggested dependence between tests 3 and 4 64.9%, 49.7%, and 49.5% of the time. We observed some variation in this across parameter settings, with these tools appearing to perform more as intended when tests 3 and 4 were both much more accurate than tests 1 and 2. Residual correlation plots, $${G}^{2}$$

G

2

and $${\chi }^{2}$$

χ

2

statistics identified a lack of overall fit in 74.3%, 64.5% and 67.5% of models, respectively. The conditional independence model tended to overestimate the sensitivities of the correlated tests (median bias across all scenarios 0.094, 2.5th and 97.5th percentiles -0.003, 0.397) and underestimate prevalence and the specificities of the uncorrelated tests.

Conclusions

Residual correlation plots and chi-squared statistics cannot be relied upon to identify which tests are conditionally dependent, and also have relatively low power to detect lack of overall fit. This is important since failure to account for conditional dependence can lead to highly biased parameter estimates.
Relationship between evaluation factors and star ratings for Japanese community healthcare institutions in electronic word-of-mouth reviews: an observational study
Authors: Maita Hiroki , Kanezaki Yuki , Akimoto Takashi , Kobayashi Tadashi , Hirano Takahiro , Kato Hiroyuki
Published: December 2024

Background

Internet reviews have become increasingly crucial for both healthcare providers and patients. Electronic word-of-mouth (eWOM) reviews on internet sites often comprise textual content with numerical ratings. In this study, we aimed to identify the evaluation factors of community healthcare institutions regarding eWOM reviews and the impact of each evaluation factor on the institution’s ratings.

Methods

An observational study was conducted to qualitatively and quantitatively analyse eWOM data posted on Google for randomly selected healthcare institutions in Hirosaki, Japan from September to October 2022. For qualitative data, the authors repeatedly read the eWOM text, coded it, and categorised related sections. For quantitative analysis, a multivariate analysis using a linear regression model was conducted with the categorised factors from the qualitative analysis as explanatory variables and eWOM ratings as response variables.

Results

Twenty medical institutions (two hospitals and 18 clinics) were randomly extracted from the registry. A total of 147 eWOM texts from each institution were analysed, and coding was performed for 474 segments in the texts. In the qualitative analysis, the evaluated factors in eWOM texts for medical institutions were categorised as communication (evaluation factor for communication with healthcare providers), clinical practice (evaluation factor for the clinical practice of healthcare providers), and medical institution (evaluation factor for the characteristics of medical institutions). According to the multiple regression analysis, the partial regression coefficients for the explanatory variables of positive communication, clinical practice, and medical institution evaluations were 1.04 (95% confidence interval 0.70 to 1.39), 0.65 (95% confidence interval 0.27 to 1.04), and 0.75 (95% confidence interval 0.35 to 1.15), respectively, with the number of ratings as the response variable. Partial regression coefficients for the explanatory variables of negative communication, clinical practice, and medical institution evaluations were − 1.52 (95% confidence interval − 1.88 to -1.16), -0.90 (95% confidence interval − 1.28 to -0.52), and − 0.24 (95% confidence interval − 0.60 to 0.12), respectively.

Conclusion

We quantitatively and qualitatively analysed the eWOM reviews and ratings of healthcare institutions posted on Google. Three evaluation factors were identified: communication, clinical practice, and medical institution. Our study revealed that communication significantly impacts ratings.
Glycemic control and associated factors in patients with type 2 diabetes in Southwest Ethiopia: a prospective observational study
Authors: Garedo Aster Wakjira , Tesfaye Gorfineh Teshome , Tamrat Rahel , Wynendaele Evelien
Published: December 2024

Background

Diabetes, a known syndrome marked by hyperglycemia and glucose intolerance, is increasing at an alarming rate worldwide. Over half a billion people worldwide have DM, and most live in low- and middle-income countries. Poor glycemic control is a public health concern in type 2 diabetes mellitus. Glycemic control and identifying factors associated with poor glycemic control can help healthcare providers design programs that improve glycemic control and the quality of services provided to patients.

Objectives

This study was designed to assess the level of glycemic control and associated factors in patients with type 2 diabetes in Jimma Medical Center, Southwest Ethiopia.

Methods

This institution-based prospective observational study was conducted among 420 patients with type 2 diabetes at Jimma Medical Center’s diabetic clinics. A pretested structured interviewer-administered questionnaire was used to collect data, and a checklist was used to assess patient documents. The data were analyzed using SPSS version 26. The variables linked to poor glycemic control were investigated using binary logistic regression. Variables with p values less than 0.05 were considered statistically significant.

Results

Six-month follow-ups were conducted among 420 patients with type 2 diabetes, among whom 220 (52.38%) were women. The median age of the participants was 54(IQR = 40–60 years old). The proportion of respondents with uncontrolled fasting blood glucose was 58.1%. Sex (AOR = 2.576, 95% CI [2.80-11.479], P = 0.001), age(≥ 60) (AOR = 2.024, 95% CI [1.794–4.646], P = 0.002), diabetes duration > 10 years (AOR = 3.036, 95% CI [2.616–8.306], P = 0.003), type 2 diabetes mellitus on insulin + oral antidiabetic (OADs) (AOR = 2.08, 95% CI [298-3.918], P = 0.004), obesity (AOR = 2.18, 95% CI [(1.218–4.218)], P = 0.003), diabetic complications (AOR = 3.193, 95% CI [2.324–6.05], p = 0.002) and poor self-care practices (AOR = 3.034, 95% CI [5.821–7.02], P = 0.005) were found to be significantly associated with poor glycemic control.

Conclusion

At the Jimma Medical Center, the prevalence of poor glycemic control was high. Based on these findings, teaching and counseling provided by healthcare providers should focus on improving diabetes self-care activities, weight reduction, and diabetic complications to achieve good glycemic control.

Clinical trial number

Not applicable.