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23 pages, 1324 KiB  
Review
Advances and Challenges in the Management of Myelodysplastic Syndromes
by Jessica M. Stempel, Tariq Kewan and Amer M. Zeidan
Cancers 2025, 17(15), 2469; https://doi.org/10.3390/cancers17152469 - 25 Jul 2025
Viewed by 962
Abstract
Myelodysplastic syndromes/neoplasms (MDS) represent a biologically and clinically diverse group of myeloid malignancies marked by cytopenias, morphological dysplasia, and an inherent risk of progression to acute myeloid leukemia. Over the past two decades, the field has made significant advances in characterizing the molecular [...] Read more.
Myelodysplastic syndromes/neoplasms (MDS) represent a biologically and clinically diverse group of myeloid malignancies marked by cytopenias, morphological dysplasia, and an inherent risk of progression to acute myeloid leukemia. Over the past two decades, the field has made significant advances in characterizing the molecular landscape of MDS, leading to refined classification systems to reflect the underlying genetic and biological diversity. In 2025, the treatment of MDS is increasingly individualized, guided by integrated clinical, cytogenetic, and molecular risk stratification tools. For lower-risk MDS, the treatment paradigm has evolved beyond erythropoiesis-stimulating agents (ESAs) with the introduction of novel effective agents such as luspatercept and imetelstat, as well as shortened schedules of hypomethylating agents (HMAs). For higher-risk disease, monotherapy with HMAs continue to be the standard of care as combination therapies of HMAs with novel agents have, to date, failed to redefine treatment paradigms. The recognition of precursor states like clonal hematopoiesis of indeterminate potential (CHIP) and the increasing use of molecular monitoring will hopefully enable earlier intervention/prevention strategies. This review provides a comprehensive overview of the current treatment approach for MDS, highlighting new classifications, prognostic tools, evolving therapeutic options, and ongoing challenges. We discuss evidence-based recommendations, treatment sequencing, and emerging clinical trials, with a focus on translating biological insights into improved outcomes for patients with MDS. Full article
(This article belongs to the Special Issue New Insights of Hematology in Cancer)
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6 pages, 454 KiB  
Case Report
ANKRD26 Gene Mutation and Thrombocytopenia—Is the Risk of Malignancy Dependent on the Mutation Variant?
by Eirik B. Tjønnfjord, Kristian Tveten, Signe Spetalen and Geir E. Tjønnfjord
Hematol. Rep. 2025, 17(4), 37; https://doi.org/10.3390/hematolrep17040037 - 24 Jul 2025
Viewed by 255
Abstract
Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid [...] Read more.
Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid malignancies. However, the extent of this oncogenic risk appears to vary between specific gene variants. Understanding the genotype–phenotype relationship is essential for patient counseling and management. This report presents a multigenerational family carrying the rare c.−118C > G variant in the 5′ untranslated region of ANKRD26, contributing to the discussion on variant-specific cancer predisposition. Case Presentation: Two sisters aged 57 and 60 presented with lifelong bleeding diathesis and moderate thrombocytopenia. Their symptoms included easy bruising, menorrhagia, and excessive postoperative bleeding. Genetic testing confirmed heterozygosity for the ANKRD26 c.−118C > G variant. Bone marrow analysis revealed abnormal megakaryopoiesis without evidence of dysplasia or somatic mutations. One sister underwent major surgery without complications when managed with prophylactic hemostatic therapy. Their family history included multiple female relatives with similar symptoms, although formal testing was limited. Notably, none of the affected individuals developed hematologic malignancy, and only one developed esophageal cancer, with no current evidence linking this variant to solid tumors. Conclusions: This case underscores the importance of distinguishing between ANKRD26 variants when assessing malignancy risk. While ANKRD26-RT is associated with myeloid neoplasms, the c.−118C > G variant may confer a lower oncogenic potential. Variant-specific risk stratification and genetic counseling are crucial for optimizing surveillance and avoiding unnecessary interventions in low-risk individuals. Full article
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14 pages, 3307 KiB  
Article
Expanding the Spectrum of CSF3R-Mutated Myeloid Neoplasm Beyond Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia: A Comprehensive Analysis of 13 Cases
by Neha Seth, Judith Brody, Peihong Hsu, Jonathan Kolitz, Pratik Q. Deb and Xinmin Zhang
J. Clin. Med. 2025, 14(15), 5174; https://doi.org/10.3390/jcm14155174 - 22 Jul 2025
Viewed by 302
Abstract
Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid [...] Read more.
Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alterations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Acute Myeloid Leukemia)
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15 pages, 307 KiB  
Article
Matrix Metalloproteinases Family Gene Polymorphisms Are Associated with Thrombosis Risk in Myeloproliferative Neoplasms
by Roberta Vadeikienė, Aistė Savukaitytė, Danguolė Laukaitienė, Rūta Dambrauskienė, Rolandas Gerbutavičius, Elona Juozaitytė and Rasa Ugenskienė
Int. J. Mol. Sci. 2025, 26(14), 6646; https://doi.org/10.3390/ijms26146646 - 11 Jul 2025
Viewed by 226
Abstract
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by excessive proliferation of one or more myeloid lineages, frequently accompanied by an elevated risk of thrombotic events. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are implicated in numerous inflammatory and vascular pathophysiological processes. [...] Read more.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by excessive proliferation of one or more myeloid lineages, frequently accompanied by an elevated risk of thrombotic events. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are implicated in numerous inflammatory and vascular pathophysiological processes. In this study, we analyzed the association between selected MMP polymorphisms, rs1799750, rs243865, rs3025058, rs3918242, and rs17576, and thrombotic risk as well as clinical characteristics in patients with MPNs. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Among the polymorphisms analyzed, a statistically significant association was identified between the MMP-9 rs3918242 CT genotype and an increased risk of arterial thrombosis (OR = 4.206, CI 1.337–13.234, p = 0.014). Moreover, rs3918242 CT was associated with thrombotic events (both arterial and venous thrombosis combined), suggesting a potential contributory role in the prothrombotic phenotype observed in MPNs (OR = 3.200, CI 1.110–9.258, p = 0.031). These findings indicate that genetic variation in MMP-9, particularly rs3918242, may serve as a predictive marker for vascular complications in MPN patients. Further studies with larger cohorts are warranted to confirm these associations and to elucidate the molecular mechanisms underlying the contribution of MMP polymorphisms to thrombosis in MPNs. Full article
20 pages, 715 KiB  
Review
Microenvironment and Tumor Heterogeneity as Pharmacological Targets in Precision Oncology
by Stelvio Tonello, Roberta Rolla, Paolo Amedeo Tillio, Pier Paolo Sainaghi and Donato Colangelo
Pharmaceuticals 2025, 18(6), 915; https://doi.org/10.3390/ph18060915 - 18 Jun 2025
Cited by 1 | Viewed by 679
Abstract
Tumor diseases are characterized by high interindividual and intratumoral heterogeneity (ITH). The development and progression of neoplasms outline complex networks of extracellular and cellular signals that have yet to be fully elucidated. This narrative review provides a comprehensive overview of the literature related [...] Read more.
Tumor diseases are characterized by high interindividual and intratumoral heterogeneity (ITH). The development and progression of neoplasms outline complex networks of extracellular and cellular signals that have yet to be fully elucidated. This narrative review provides a comprehensive overview of the literature related to the cellular and molecular mechanisms underlying the heterogeneity of the tumor mass. Furthermore, it examines the possible role of the tumor microenvironment in the development and support of the neoplasm, in order to highlight its potential in the construction of a diagnostic–therapeutic approach to precision medicine. Many authors underline the importance of the tumor microenvironment (TME) as it actively takes part in the growth of the neoplastic mass and in the formation of metastases and in the acquisition of resistance to anticancer drugs. In specific body districts, the ideal conditions occur for the TME establishment, particularly the inflammatory state, the recruitment of cell types, the release of specific cytokines and growth factors, hypoxic conditions. These components actively intervene by enabling tumor progression and construction of physical barriers shaped by the extracellular matrix that contribute to forming peripheral tolerance by intervention of myeloid precursors and the polarization of M2 macrophages. In recent years, ITH and the TME have assumed an important position in cancer research and pharmacology as they enable understanding the dense network of communication existing between the neoplasm and the surrounding environment, and to monitor and deepen the effects of drugs with a view to develop increasingly precise and effective therapies. In the last decade, knowledge of TME has been exploited to produce targeted molecular agents (inhibitory small molecules, monoclonal antibodies, gene therapy). Nonetheless, the bibliography shows the need to study ITH through new prognostic and predictive biomarkers (e.g., ctDNA and CTCs) and to increase its basic biology knowledge. Precision medicine is a new opportunity in the treatment of oncological diseases that is transforming the development of new drug approaches and their clinical use. Biology and biotechnologies are providing the bases for this revolution. Full article
(This article belongs to the Section Pharmacology)
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10 pages, 525 KiB  
Review
Myeloid and Lymphoid Malignancies with Fusion Kinases Involving Spleen Tyrosine Kinase (SYK)—Emerging Rare Entities?
by Velizar Shivarov and Stefan Lozenov
Hemato 2025, 6(2), 17; https://doi.org/10.3390/hemato6020017 - 14 Jun 2025
Viewed by 399
Abstract
Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK [...] Read more.
Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article
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34 pages, 423 KiB  
Review
Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms
by Le Wang, Julie Li, Leah Arbitman, Hailing Zhang, Haipeng Shao, Michael Martin, Lynn Moscinski and Jinming Song
Cancers 2025, 17(11), 1834; https://doi.org/10.3390/cancers17111834 - 30 May 2025
Viewed by 1298
Abstract
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red [...] Read more.
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article
19 pages, 768 KiB  
Article
From Sanger to Oxford Nanopore MinION Technology: The Impact of Third-Generation Sequencing on Genetic Hematological Diagnosis
by María José Larráyoz, Pablo Luri-Martin, Amagoia Mañu, Oihane Churruca, Natalia Gordillo, Irache Erdozain, Ada Esteban-Figuerola, Carlos de Miguel, Diego Robles, María García-Fortes, José Rifón Roca, Ana Alfonso-Pierola, Felipe Prósper, Beñat Ariceta and María José Calasanz
Cancers 2025, 17(11), 1811; https://doi.org/10.3390/cancers17111811 - 29 May 2025
Viewed by 786
Abstract
Background: Sanger sequencing remains the gold standard for characterizing genetic variants in short DNA fragments (<700 bp). However, the increasing demand for short TATs and high sensitivities in variant detection, particularly in oncohematology, is driving the need for more efficient methods. Next-generation sequencing [...] Read more.
Background: Sanger sequencing remains the gold standard for characterizing genetic variants in short DNA fragments (<700 bp). However, the increasing demand for short TATs and high sensitivities in variant detection, particularly in oncohematology, is driving the need for more efficient methods. Next-generation sequencing (NGS) has improved sensitivity and allows for the simultaneous analysis of multiple genes, but it is still costly and time-consuming. Consequently, Sanger sequencing continues to be widely used. In this study, we have compared Sanger sequencing with Oxford Nanopore technology (ONT), which offers enhanced sensitivity and faster sequencing, delivering diagnostic results within 24 h. Methods: This study involves 164 samples (for a total of 174 analyzed regions of interest) previously characterized using either Sanger sequencing or a next-generation sequencing (NGS) panel, categorized by their genetic alterations. Validation was conducted on 15 genes crucial for the diagnosis, prognosis, or identification of drug resistance in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). The primary objective was to assess whether MinION could identify the same variants previously detected in these patients. Results and Conclusions: With a 99.43% concordance observed in our comparison, our results support the implementation of MinION technology in routine variant detection in MPN, MDS, AML, and CML cases due to its significant advantages over Sanger sequencing. Full article
(This article belongs to the Special Issue Long-Read Sequencing in Cancer)
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20 pages, 2793 KiB  
Article
High Burden of Non-Clonal Chromosome Aberrations Before Onset of Detectable Neoplasia in Fanconi Anemia Bone Marrow
by Silvia Sánchez, Benilde García-de-Teresa, Marco A. Mejía-Barrera, Pedro V. Reyes-Jiménez, Antonio Paz-Martínez, Miguel A. Martínez, Moisés Ó. Fiesco-Roa, Angélica Monsiváis-Orozco, Bertha Molina, Leda Torres, Alfredo Rodríguez and Sara Frias
Cancers 2025, 17(11), 1805; https://doi.org/10.3390/cancers17111805 - 28 May 2025
Viewed by 971
Abstract
Background/objectives: Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow [...] Read more.
Background/objectives: Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and are associated with MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCAs) are expected to be common events in the FA BM; in this study, we investigated the presence and significance of NCCA and CCA in the bone marrow (BM) of patients with FA. Methods: Here, we transversally examined the BM karyotypes of 43 non-transplanted patients with FA, 41 with non-clinically detectable hematologic neoplasia and two with diagnosed MDS. We searched for the presence of NCCAs, complex karyotypes (CKs), and CCAs as well as their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation. Results: NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients; CCAs were found in 15/43 patients; CCAs involving chromosomes 1, 3 and/or 7 were found in four patients; and other autosomes were found in the remaining 11 patients. Overall, we observed a baseline large karyotypic heterogeneity in the BM of FA patients, demonstrated by the ubiquitous presence of NCCA; such karyotypic heterogeneity precedes the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. Overall, we observed that the frequency of NCCAs and CCAs increased with age, even though a significant correlation was not found. Conclusions: These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCAs and karyotypic heterogeneity, followed by the establishment of clones with CCAs, leading to microevolution and cancer. NCCAs are the most frequent chromosomal alterations in the bone marrow of patients with AF and constitute a genome with extensive karyotypic heterogeneity that evolves into clones with more complex genomes and can eventually progress to cancer. Full article
(This article belongs to the Special Issue The Role of Chromosomal Instability in Cancer: 2nd Edition)
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17 pages, 4071 KiB  
Article
Examining the Effects of the RUNX1 p.Leu43Ser Variant on FPD/AML Phenotypes Using a CRISPR/Cas9-Generated Knock-In Murine Model
by Ana Marin-Quilez, Ignacio García-Tuñón, Rocío Benito, José Luis Ordoñez, Lorena Díaz-Ajenjo, Ana Lama-Villanueva, Carmen Guerrero, Jesús Pérez-Losada, José Ramón González-Porras, Jesús María Hernández-Rivas, Mónica del Rey and José María Bastida
Biomolecules 2025, 15(5), 708; https://doi.org/10.3390/biom15050708 - 12 May 2025
Viewed by 545
Abstract
Germline heterozygous variants in RUNX1 lead to Familial Platelet Disorder with Myeloid Leukemia Predisposition (FPD/AML). Cellular and/or animal models are helpful to uncovering the role of a variant in disease progression. Twenty-five mice per genotype (RUNX1WT/WT, RUNX1WT/L43S, RUNX1L43S/L43S [...] Read more.
Germline heterozygous variants in RUNX1 lead to Familial Platelet Disorder with Myeloid Leukemia Predisposition (FPD/AML). Cellular and/or animal models are helpful to uncovering the role of a variant in disease progression. Twenty-five mice per genotype (RUNX1WT/WT, RUNX1WT/L43S, RUNX1L43S/L43S), previously generated by CRISPR/Cas9, and nine sub-lethally irradiated mice per genotype were investigated. Peripheral blood (PB), bone marrow (BM), and spleen samples were analyzed by flow cytometry and histopathology. Deregulated genes were analyzed by RNA-seq in BM. An aberrant myeloid Mac1+Sca1+ckit population in the PB, BM, and spleen of two homozygous and one heterozygous mouse was observed, as well as BM hypercellularity. No Mac1+Sca1+ckit cells were detected in any RUNX1WT/WT mice. Moreover, the spleen of both homozygous mice showed destruction of the white/red pulp and the presence of apoptotic cells. The aberrant population was also detected in four irradiated mice, two heterozygous and two homozygous, in their PB, BM, and spleen. RNA-seq studies showed 698 genes significantly deregulated in the three non-irradiated Mac1+Sca1+ckit mice vs. six healthy mice, highlighting the alteration of genes involved in apoptosis and DNA repair. These results indicate that the homozygous form of the variant p.Leu43Ser may contribute to the pathogenesis of aberrant cells. Full article
(This article belongs to the Special Issue Molecular Advances in Platelet Disease, Thrombosis and Hemostasis)
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11 pages, 1418 KiB  
Article
The Role of BCL-2 Expression in Patients with Myelodysplastic Neoplasms
by Bartłomiej Kuszczak, Krzysztof Zduniak, Angela Jendzierowska, Tomasz Wróbel, Piotr Ziółkowski and Justyna Rybka
Curr. Issues Mol. Biol. 2025, 47(5), 346; https://doi.org/10.3390/cimb47050346 - 10 May 2025
Viewed by 491
Abstract
Myelodysplastic neoplasms (MDS) represent a heterogeneous group of neoplastic bone marrow disorders. A crucial component in regulating bone marrow cell apoptosis is the B-cell CLL/lymphoma 2 (BCL-2) protein. This retrospective study aimed to assess BCL-2 expression by immunohistochemistry in trephine biopsy specimens from [...] Read more.
Myelodysplastic neoplasms (MDS) represent a heterogeneous group of neoplastic bone marrow disorders. A crucial component in regulating bone marrow cell apoptosis is the B-cell CLL/lymphoma 2 (BCL-2) protein. This retrospective study aimed to assess BCL-2 expression by immunohistochemistry in trephine biopsy specimens from 76 patients diagnosed with MDS. The obtained retrospective results were correlated with clinical parameters, including age, sex, MDS subtype, IPSS, IPSS-R, bone marrow blast percentage, Ogata score, response to treatment, blood morphology parameters, and overall survival (OS). The median follow-up duration was 16 months. During the observation period, 58 patients died (median OS of this group: 14.6 months), and 25 patients experienced progression to acute myeloid leukemia. The median BCL-2 expression assessed using the Histoscore (H-score) was 10. Patients with BCL-2 expression below 10 had better survival outcomes than those with expression ≥ 10. Furthermore, patients without detectable BCL-2 expression had significantly better survival compared to those with detectable BCL-2 expression (p = 0.0084). Higher BCL-2 expression was significantly associated with high and very high cytogenetic risk, as defined by IPSS-R. BCL-2 immunohistochemistry should be viewed as a complementary biomarker that, when integrated with IPSS-R and mutational data, could refine therapeutic algorithms. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)
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8 pages, 1036 KiB  
Brief Report
Clinical Outcome and Molecular Profile in Patients with DDX41 Mutation Hot-Spots
by Nadia Toumeh, Yazan Jabban, Ahmad Nanaa, Rong He, David Viswanatha, Dragan Jevremovic, James M. Foran, Cecilia Y. Arana Yi, Antoine N. Saliba, Mehrdad Hefazi Torghabeh, William J. Hogan, Mithun V. Shah, Abhishek A. Mangaonkar, Mrinal M. Patnaik, Hassan B. Alkhateeb and Aref Al-Kali
Hematol. Rep. 2025, 17(3), 26; https://doi.org/10.3390/hematolrep17030026 - 8 May 2025
Viewed by 633
Abstract
Background/Objectives: DDX41, DEAD-box RNA helicase 41 gene located on chromosome 5q25.3, is one of the most mutated genes in patients with germline predisposition to myeloid neoplasms. Germline and somatic mutations often have different locations and patterns of mutation, with some hotspots [...] Read more.
Background/Objectives: DDX41, DEAD-box RNA helicase 41 gene located on chromosome 5q25.3, is one of the most mutated genes in patients with germline predisposition to myeloid neoplasms. Germline and somatic mutations often have different locations and patterns of mutation, with some hotspots displaying diversity based on ethnicity. We aimed to explore clinical outcomes in patients with various DDX41 hot-spot mutations. Methods: This was a retrospective study of patients at Mayo Clinic with DDX41 mutation identified through Next Generation Sequencing (NGS) between 2018 and 2024. We completed unadjusted comparisons using continuous or categorical variables, and survival rates were assessed using the Kaplan–Meier method and cox regression analysis. Results: Overall survival appears to be higher in those with p.M1| when compared to p.Asp140GlyFs*2 and p.Arg525His, with comparable survival between p.Arg525His and p.Asp140GlyFs*2. Among males with p.M1| who underwent bone marrow transplant, those who underwent bone marrow transplant appeared to have lower survival rates, although not statistically significant. Our study was limited by a small sample size, therefore limiting our ability to reach significance. Conclusions: Our findings suggest potential implications for clinical outcomes based on DDX41 mutation hot-spots. Full article
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22 pages, 4080 KiB  
Article
Cancer Burden in Adolescents and Young Adults in Belgium: Trends to Incidence Stabilisation in Recent Years with Improved Survival
by Fabienne Van Aelst, Bart Van Gool, Nancy Van Damme and Hélène A. Poirel
Cancers 2025, 17(9), 1543; https://doi.org/10.3390/cancers17091543 - 1 May 2025
Viewed by 1092
Abstract
Background/Objectives: This population-based study examined epidemiological trends of primary cancers in adolescents and young adults (AYAs) to enhance the understanding of the specific spectrum of cancers impacting AYAs in Belgium. Methods: Data on incidence, prevalence, mortality, and survival were obtained from [...] Read more.
Background/Objectives: This population-based study examined epidemiological trends of primary cancers in adolescents and young adults (AYAs) to enhance the understanding of the specific spectrum of cancers impacting AYAs in Belgium. Methods: Data on incidence, prevalence, mortality, and survival were obtained from the Belgian Cancer Registry (2004–2020, N = 43,535). (A)APC statistics were compared with children (5–14 years) and adults (40–49 years). Results: Cancer incidence increased by 0.4% annually from 66 to 80 per 100,000 person-years (ESR2013) but stabilised after 2015, except for Hodgkin lymphoma, chronic myeloid neoplasms, and testicular and breast cancer, which continued to rise. Mortality decreased by 1% annually, from 10 to 7 per 100,000 person-years (2004–2019). Five-year relative survival (RS) was 87% but remained low for certain cancers, including ovary (78%), central nervous system (67%), precursor haematopoietic neoplasms (64%), gastrointestinal (excl. colorectal) (49%), and lung-bronchus-trachea cancers (42%). Conclusions: From 2004–2020, the cancer burden among AYAs in Belgium increased due to improved survival, while incidence stabilised after 2015. Five-year RS exceeds 80% overall but remains lower for some cancers compared to children (e.g., precursor haematopoietic neoplasms) or older adults (e.g., breast cancer, sarcoma). The Belgian epidemiological trends align with those in neighbouring countries (Netherlands, France, Germany). Full article
(This article belongs to the Section Pediatric Oncology)
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15 pages, 1577 KiB  
Article
Clinical Utility of Optical Genome Mapping as an Additional Tool in a Standard Cytogenetic Workup in Hematological Malignancies
by Gokce A. Toruner, Shimin Hu, Sanam Loghavi, Chi Young OK, Zhenya Tang, Qing Wei, Rashmi Kanagal-Shamanna, L. Jeffrey Medeiros and Guilin Tang
Cancers 2025, 17(9), 1436; https://doi.org/10.3390/cancers17091436 - 25 Apr 2025
Cited by 1 | Viewed by 942
Abstract
Background and Objective: The primary objective of this study is to evaluate the added value of optical genome mapping (OGM) when integrated into the standard cytogenetic workup (SCGW) for hematological malignancies. Methods: The study cohort comprised 519 cases with different types of hematological [...] Read more.
Background and Objective: The primary objective of this study is to evaluate the added value of optical genome mapping (OGM) when integrated into the standard cytogenetic workup (SCGW) for hematological malignancies. Methods: The study cohort comprised 519 cases with different types of hematological malignancies. OGM and SCGW (including G-banded karyotyping and fluorescence in situ hybridization) were performed on blood and/or bone marrow. The analytical sensitivity of OGM, defined as the detection of all additional cytogenomic aberrations, and its clinical utility, referring to aberrations with diagnostic, prognostic, or therapeutic significance, were assessed. Results: OGM led to increased analytical sensitivity and clinical utility in 58% and 15% of the cases, respectively. The clinical utility varied across different malignancies, with the highest utility in T-lymphoblast leukemia (52%), followed by mixed phenotype acute leukemia (43%), B-lymphoblastic leukemia (37%), other B-cell lymphomas (22%), mature T-cell leukemia/lymphoma (20%), chronic lymphocytic leukemia (14%), acute myeloid leukemia (13%), multiple myeloma (13%), mantle cell lymphoma (8%), myelodysplastic/myeloproliferative neoplasms (6%), myelodysplastic syndrome (5%), and myeloproliferative neoplasms (0%). Conclusion: Compared to SCGW, OGM detects additional cytogenomic aberrations in approximately 58% of cases. OGM provides clinical utility at varying rates across different types of hematological malignancies. Given these differences, strategic triaging can help maximize the clinical value of OGM by focusing on diseases where it offers the most significant benefit. Full article
(This article belongs to the Special Issue Diagnostic Biomarkers in Cancers Study)
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15 pages, 2725 KiB  
Article
Comparison of the Hematotoxicity of PRRT with Lutathera® and Locally Manufactured 177Lu-HA-DOTATATE in Patients with Neuroendocrine Tumors and the Impact of Different Application Intervals
by Markus Hofmann, Sophie C. Kunte, Marcus Unterrainer, Astrid Delker, Adrien Holzgreve, Johannes Toms, Franz Joseph Gildehaus, Christoph J. Auernhammer, Christine Spitzweg, Mathias J. Zacherl, Harun Ilhan, Johannes Rübenthaler, Leonie Beyer and Lena M. Unterrainer
Cancers 2025, 17(9), 1423; https://doi.org/10.3390/cancers17091423 - 24 Apr 2025
Cited by 2 | Viewed by 868
Abstract
Background/Objectives: Peptide Receptor Radionuclide Therapy (PRRT) is approved for patients with inoperable, progressive and/or metastatic well-differentiated NETs. Before the approval of Lutathera®, locally manufactured 177Lu-HA-DOTATATE was used on a regular basis in clinical routine. The aim of this study was [...] Read more.
Background/Objectives: Peptide Receptor Radionuclide Therapy (PRRT) is approved for patients with inoperable, progressive and/or metastatic well-differentiated NETs. Before the approval of Lutathera®, locally manufactured 177Lu-HA-DOTATATE was used on a regular basis in clinical routine. The aim of this study was (1) to compare the hematotoxicity of locally manufactured 177Lu-HA-DOTATATE with Lutathera® in GEP-NET patients and (2) to compare the recommended treatment interval of 8 weeks between each cycle to a prolonged scheme of up to 11 weeks for both 177Lu-HA-DOTATATE and Lutathera®. Methods: The included patients with GEP NETs (n = 46) received four cycles of PRRT, either 177Lu-HA-DOTATATE or Lutathera®, and were divided into four subgroups. The subgroups were treated with either locally manufactured 177Lu-HA-DOTATATE or Lutathera® and were stratified into a mean application interval of 8 (HA8weeks, n = 10/Lutathera8weeks, n = 16) or 11 weeks (HAadapted, n = 10/Lutatheraadapted, n = 10). To evaluate therapy associated hemato- and nephrotoxicity, patients underwent two laboratory follow-up examinations (follow-up 1—between 2./3. therapy cycle; follow-up 2—after the termination of the 4. therapy cycle) and were then compared to pre-PRRT laboratory results. To assess hematological and renal recovery trends, blood values and parameters of kidney function were collected up to 58.9 weeks after PRRT completion. Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) were used for grading hematological parameters. Results: The occurrence of high-grade adverse events (CTCAE grade 3/4) after PRRT was moderate, with 1/10 (10%) grade 4 lymphocytopenia in the Lutatheraadapted group, while overall, 20/46 (43.5%) patients had grade 3 lymphocytopenia. Grade 3 thrombocytopenia occurred in 1/10 (10%) patients of the HAadapted group. Absolute and percentage changes in the kidney function (creatinine, TER) remained constant during PRRT in all subgroups. All four subgroups showed a significant decrease in absolute blood value changes for PLT counts, WBC counts, neutrophil granulocytes and lymphocytes between, prior to and after PRRT (p < 0.05, each). Regarding percentage changes in laboratory parameters, only the HAadapted and the HA8weeks groups had significant decreases in WBC (p < 0.03, each) and PLT counts (p < 0.04, each) while there was no significant degradation of any other hematological parameter in any of the subgroups. Only patients with longer treatment intervals under 177Lu-HA-DOTATATE therapy showed a statistically significant correlation in the long-term recovery analysis concerning the PLT counts (r = 0.6, p < 0.0001). Other blood and kidney values showed no significant correlation in the long-term analysis in the other subgroups. Conclusion: Comparing the hematotoxicity in patients that were treated with locally manufactured 177Lu-HA-DOTATATE with patients that were treated with Lutathera® and assessing different treatment intervals in both groups (8 vs. 11 weeks), revealed that there is overall a low to moderate incidence of significant changes in hematological and renal parameters directly after PRRT. Recovery trends of hematological and renal parameters after 1 year suggest that patients treated with locally manufactured 177Lu-HA-DOTATATE might benefit from a longer treatment interval of 11 weeks regarding their PLT counts. Given the risk of developing hematological diseases such as therapy-related myeloid neoplasms years after PRRT, longer observational periods after PRRT will be crucial. Full article
(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Germany)
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