Search Results (375)

Background: Anthracycline-based chemotherapy is associated with a risk of cancer therapy-related cardiac dysfunction (CTRCD), particularly in patients with moderate to high cardiovascular risk. Left ventricular global longitudinal strain (GLS) is a sensitive marker for early myocardial dysfunction, but the prognostic value of baseline GLS in this population remains unclear. Objective: We aimed to evaluate whether baseline GLS can predict CTRCD in moderate- to high-risk cancer patients undergoing anthracycline chemotherapy. Methods: In this prospective, single-center observational study, 80 anthracycline-naive cancer patients classified as moderate or high risk were enrolled. Baseline GLS was assessed via speckle-tracking echocardiography, with a threshold of ≥−18% considered decreased. Patients were followed for 12 months, and the primary endpoint was the development of CTRCD per ESC 2022 Cardio-oncology guidelines. Results: Of the 77 patients completing follow-up, 27.3% had decreased baseline GLS. CTRCD occurred in 62.4% of patients, with higher incidence among those with decreased GLS (76.7%) compared to those with normal GLS. In multivariable analysis, GLS ≥−18% was the only significant independent predictor of CTRCD (RR 12.0, 95% CI 2.0–71.9; p = 0.0065). All-cause mortality was also significantly higher in patients with decreased baseline GLS (19.1% vs. 1.8%, p = 0.018). Conclusions: Decreased baseline global longitudinal strain is an independent predictor of cancer therapy-related cardiac dysfunction and all-cause mortality in moderate- to high-risk patients receiving anthracycline therapy. These findings support the inclusion of baseline GLS in pre-treatment cardiovascular risk assessment, particularly in patients with an LVEF above 54%, to more effectively identify those who may benefit from early cardioprotective interventions. Full article

Background: Immunodeficiencies are a heterogeneous group of disorders classified etiologically as primary (congenital) or secondary (acquired). Primary immunodeficiencies (PIDs), such as common variable immunodeficiency (CVID), result from genetic mutations that impair the development and function of lymphocytes. Secondary immunodeficiencies (SIDs) arise as a consequence of chronic diseases, lymphoid malignancies, or immunosuppressive therapies. Aim of the study: The purpose of this study was to assess the serum expression profile of selected microRNAs (miRNAs) in patients with CVID and in those with chronic lymphocytic leukemia (CLL) and coexisting SID, compared to healthy individuals. Methods: Digital PCR (dPCR) was applied to quantify the serum expression levels of selected miRNAs in patients with CVID, patients with CLL and SID, and in healthy controls. Results: dPCR revealed significantly reduced levels of miR-16, miR-30c, miR-181a, miR-29a, miR-150, and miR-326 in the CVID group, potentially reflecting impaired regulatory mechanisms of the immune system. In contrast, elevated levels of miR-21, miR-125b, and miR-155 were observed in the CLL group with SID, suggesting their role in tumorigenesis and secondary immunosuppression. Correlations between miRNA levels and the expression of immune checkpoints (PD-1, CTLA-4, CD200) indicated the involvement of a complex regulatory network encompassing both humoral and cellular immune mechanisms. Conclusions: The results provide preliminary evidence that selected miRNAs could reflect disease-specific immune dysregulation patterns and may hold potential as diagnostic and prognostic biomarkers in both PIDs and SIDs. Full article

Gastrointestinal (GI) lymphomas are a diverse group of extranodal non-Hodgkin lymphomas primarily affecting the stomach, small intestine, and colon. They present with non-specific symptoms such as abdominal pain, weight loss, or GI bleeding, making early diagnosis challenging. Histologic subtypes vary, with mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common. Diagnosis involves endoscopic evaluation with biopsy, cross-sectional imaging, and often PET-CT. Management is subtype-dependent, including antibiotics for H. pylori-associated MALT lymphoma, chemotherapy, immunotherapy, and occasionally surgery. A multidisciplinary approach is essential for optimal outcomes. Core Tip: Gastrointestinal lymphomas are rare but clinically significant malignancies with variable presentations. Accurate diagnosis and tailored treatment based on the histologic subtype and site are critical, requiring close collaboration among gastroenterologists, pathologists, oncologists, and radiologists. Full article

Background/Objective: US military personnel deployed to the Middle East were potentially subjected to harmful exposures, such as carcinogens from burn pits, which may increase the risk of lymphoid malignancies. Our objective was to determine the association between deployment and the risk of developing lymphoid malignancies. Methods: This was a retrospective nested matched case-control study from a cohort of 3.5 million veterans who enlisted in the military after September 2001 and were followed until death or last follow up through September 2024. Cases of lymphoid malignancies were identified by the VA Central Cancer Registry and controls were randomly selected from the same base cohort, matched by year of birth, year of enlistment, sex, race, and ethnicity. Exposure was defined as deployment to the Middle East as determined by identification on the VA Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) roster with confirmed dates of deployment or paystubs. Results: There were 1037 cases of lymphoid malignancies and 3572 matched controls. Deployment was not associated with a higher risk of developing lymphoid malignancies compared to non-deployment. Exposure to OEF/OIF was not associated with a higher risk of developing certain types of lymphoid malignancies. Conclusions: In this large, matched case-control study of US veterans, deployment to the Middle East was not associated with increased risk of developing lymphoid malignancies. While these findings do not support an increased lymphoid malignancy risk, important limitations remain, including the absence of detailed exposure and potential confounding variables. Prospective monitoring of specific types and doses of exposures during military deployment, development of lymphoid and other malignancies, and their underlying pathophysiology is indicated. Full article

The intracellular topography of RNA molecules, encompassing ribonucleotides with biochemical modifications, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), adenosine to inosine (A → I) editing, and isomerization of uridine to pseudouridine (Ψ), as well as of non-coding RNA molecules, is currently studied within the frame of the epigenome. Circulating RNA molecules in the intracellular space that have incorporated information by carrying specific modifications depend on the balanced activity and correct subcellular installation of their modifying enzymes, the “writers”, “readers” and “erasers”. Modifications are critical for RNA translocation from the nucleus to the cytoplasm, for stability and translation efficiency, and for other, still-uncovered functions. Moreover, trafficking of non-coding RNA molecules depends on membrane transporters capable of recognizing signal sequences and RNA recognition-binding proteins that can facilitate their transport to different intracellular locations, guiding the establishment of interconnection possibilities with different macromolecular networks. The potential of long non-coding RNAs to form multilayer molecular connections, as well as the differential topology of micro-RNAs in cell nuclei, compared to cytoplasm, has been recognized by several studies. The study of the intercellular compartmentalization of these molecules has recently become feasible thanks to technological progress; however, a wealth of information has not yet been produced that would lead to safe conclusions regarding non-coding RNA’s contributions to the early steps of pathogenesis and disease progression in hematological malignancies. Both, the bone marrow, as the main hematopoietic tissue, and the lymphoid tissues are composed of cells with highly reactive potential to signals affecting the epigenome and initiating cascade pathways in response. Independently or in combination with coexistent driver genetic mutations, especially mutations of enzymes involved in epigenomic surveillance, intracellular microenvironmental alterations within the cell nuclear, cytoplasmic, and mitochondrial compartments can lead to disorganization of hematopoietic stem cells’ epigenomes, promoting the generation of hematological malignancies. In this review, we discuss the various intracellular processes that, when disrupted, may result in the ectopic placement of RNA molecules, either inducing specific modifications or non-coding molecules or promoting hematological malignant phenotypes. The crosstalk between mitochondrial and nuclear genomes and the complex regulatory effects of mis-localized RNA molecules are highlighted. This research approach may constitute a field for new, more specifically targeted therapies in hematology based on RNA technology. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous malignancy, characterized by low tumor cellularity, a dense stromal response, and intricate cellular and molecular interactions within the tumor microenvironment (TME). Although bulk omics technologies have enhanced our understanding of the molecular landscape of PDAC, the specific contributions of non-malignant immune and stromal components to tumor progression and therapeutic response remain poorly understood. Methods: We explored genome-wide DNA methylation and transcriptomic data from the Cancer Genome Atlas Pancreatic Adenocarcinoma cohort (TCGA-PAAD) to profile the immune composition of the TME and uncover gene co-expression networks. Bioinformatic analyses included DNA methylation profiling followed by hierarchical deconvolution, epigenetic age estimation, and a weighted gene co-expression network analysis (WGCNA). Results: The unsupervised clustering of methylation profiles identified two major tumor groups, with Group 2 (n = 98) exhibiting higher tumor purity and a greater frequency of KRAS mutations compared to Group 1 (n = 87) (p < 0.0001). The hierarchical deconvolution of DNA methylation data revealed three distinct TME subtypes, termed hypo-inflamed (immune-deserted), myeloid-enriched, and lymphoid-enriched (notably T-cell predominant). These immune clusters were further supported by co-expression modules identified via WGCNA, which were enriched in immune regulatory and signaling pathways. Conclusions: This integrative epigenomic–transcriptomic analysis offers a robust framework for stratifying PDAC patients based on the tumor immune microenvironment (TIME), providing valuable insights for biomarker discovery and the development of precision immunotherapies. Full article

Non-Hodgkin B-cell lymphomas are a heterogeneous group of lymphoid malignancies with variable biological behavior, clinical presentation and treatment response. While chemoimmunotherapy remains the cornerstone of their management, growing evidence implicates the gut microbiota as a critical modulator of both lymphomagenesis and therapeutic efficacy. Gut microbiota dysbiosis, characterized by reduced microbial diversity and pathogenic taxonomic shifts, has been observed also in newly diagnosed patients and not just after therapy. This microbial imbalance contributes to mucosal barrier disruption, systemic inflammation, and altered immune responses, affecting treatment outcomes and toxicity profiles. Antibiotic exposure, especially broad-spectrum agents, exacerbates dysbiosis and has been associated with inferior responses to immunochemotherapy and CAR T-cell therapy. Conversely, certain commensal taxa, like Faecalibacterium prausnitzii and Lactobacillus johnsonii, may exert protective effects by preserving mucosal homeostasis and promoting antitumor immunity. Targeted interventions, including prudent antibiotic stewardship, prebiotics, probiotics, dietary modulation, and fecal microbiota transplantation, are under investigation to restore eubiosis and improve clinical outcomes. Preliminary clinical trials suggest a strong correlation between baseline microbiome composition and therapeutic response. Further mechanistic studies and randomized trials are warranted to define the causal role of the microbiome in non-Hodgkin B-cell lymphomas pathophysiology and to develop personalized microbiome-modulating strategies as adjuncts to standard treatment. Full article

Background and Clinical Significance: Granulomatosis with polyangiitis (GPA), an immune-mediated systemic small-vessel vasculitis affecting the upper/lower respiratory tracts and kidneys, frequently presents with non-specific nasal symptoms that lead to misdiagnosis. Case Presentation: We report a case of a 55-year-old female with GPA complicated by Bartter syndrome. She presented with one month of left nasal congestion, rhinorrhea, epistaxis, and headache. Initial diagnosis was acute sinusitis. Computed tomography (CT) revealed left maxillary and ethmoid sinus inflammation with bone destruction, while metagenomic next-generation sequencing (mNGS) suggested conventional bacterial infection. Postoperative pathology demonstrated chronic mucosal inflammation with lymphoid tissue hyperplasia. GPA was ultimately diagnosed based on PR3-ANCA seropositivity and chest CT findings of cavitary pulmonary nodules. Postoperatively, severe hypokalemia and hypomagnesemia secondary to Bartter syndrome emerged. Following electrolyte correction, induction therapy with glucocorticoids and cyclophosphamide was initiated. Conclusions: This case underscores that GPA’s head and neck manifestations are frequently misdiagnosed as infections or malignancies. Early diagnosis requires vigilance for GPA ‘red flags’, such as refractory nasal symptoms to conventional therapy (e.g., bloody rhinorrhea), characteristic CT findings (e.g., sinus opacification without ostiomeatal complex obstruction), and nasal endoscopy findings (e.g., ulcers/crusting). Otolaryngologists play a pivotal role in recognizing early disease onset and initiating timely treatment. Full article

Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential. Full article

Inhibitors of the tyrosine kinase Zap70 are actively searched to improve treatments of lymphoid malignancies and autoimmune diseases associated with an abnormal T-cell response. The natural product withaferin A (WFA) has been characterized as a covalent inhibitor of Zap70 capable of blocking the migration of human T-cells. By analogy, we postulated that other withanolides equipped with a thiol-reactive, α,β-unsaturated ketone may form covalent complexes with Zap70. The hypothesis was tested using a molecular modeling approach with a panel of 12 withanolides docked onto the kinase domain of Zap70. Seven natural products revealed a capability to form stable complexes with Zap70 comparable to that of WFA, including withangulatin A, 4β-hydroxywithanolide E, withaperuvin, and ixocarpalactone A. Withangulatin A surpassed all the other withanolides for its ability to engage an interaction with Zap70 kinase and to form covalent complexes via bonding to the Cys346 residue close to the enzyme active site. The physicochemical and ADMET properties of withangulatin A were analyzed via Density Functional Theory calculations and an analysis of its Fukui function descriptors. The C3 position of the enone moiety was identified as the most reactive (nucleophilic) site of the molecule. Withangulatin A revealed a satisfactory ADMET profile with no major toxicity anticipated. It represents a potential hit to guide the design of Zap70 inhibitors. Full article

Purpose: Evaluate long-term immunogenicity and its association with the number of vaccines and breakthrough infections in patients with hematologic malignancies compared to a healthy cohort. Methods: This study is an amendment of a multicenter study (DRKS00027372) which described the upsurge of anti-spike-IgGs on day 120 from a blunted day-35 response in patients with hematologic neoplasms. In this amendment, 191 individuals from the original study (patients with myeloid and lymphoid neoplasms and controls) were followed beyond month 12 after first SARS-CoV-2-vaccination. The long-term humoral and cellular responses and their correlation with the number of vaccines were studied. Results: After a median follow-up of 18 months, a median of three vaccinations (range 1–5) were given. Antibody levels did not correlate with the number of vaccinations (≤2 versus ≥3) (p = 0.3). With a median of 5274 U/mL anti-spike-IgGs, the inferior day-120 antibody response in patients with lymphoid neoplasms was no longer detected. Breakthrough SARS-CoV-2-infections, mostly mild, occurred in 67% of controls and 46% of patients. Patients with lymphoid neoplasms with two vaccinations did not have more infections compared to patients with more doses (p = 0.4). There was a significant decline in the spike-specific T-cell response for CovCD4⁺ and CovCD8⁺ (p < 0.001). On last assessment, 33% of individuals lost their day-120 CovCD4⁺-positive response (p < 0.001). There was no correlation between the number of vaccinations and cellular immune response in patients and controls (p = 0.3). Conclusions: In this study, breakthrough infections were high despite repeated boosting, which by itself does not lead to an upsurge in the cellular immune response in the majority of patients. Full article

The role of HAT-PCR (High A/T or High Annealing Temperature–PCR) in the quantification of minimal residual disease (MRD) was investigated in chronic lymphocytic leukemia (CLL) and myeloma. The IGH gene sequence was determined by next-generation sequencing (NGS), either by the Lymphotrack kit or by preparing libraries using an in-house two-round PCR protocol which enabled successful sequencing in 37/37 CLL marrow samples and 34/35 myeloma marrow samples. MRD was quantified by HAT-PCR in 125 CLL marrow or blood samples from 36 patients, with 2 results being less than 10⁻⁶ and in 63 myeloma marrow samples from 35 patients, with 10 results being less than 10⁻⁶. Measurement of MRD in 113 pairs of CLL samples and 51 pairs of myeloma samples showed that HAT-PCR was significantly more sensitive than flow. Compared to marrow MRD, blood MRD was relatively high in CLL but very low or undetectable in myeloma. Flow-positive HAT-PCR negative samples were not seen in myeloma, although the literature review suggested that flow-positive NGS-negative myeloma samples are sometimes observed. The ability of HAT-PCR to quantify down to and below 10⁻⁶ and the practical advantages of PCR suggest that HAT-PCR could be used widely for the quantification of MRD in lymphoid malignancy. Full article

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy defined by the uncontrolled proliferation of lymphoid precursors. Accurate diagnosis and effective therapeutic strategies hinge on a comprehensive understanding of the genetic and molecular landscape of ALL. This review synthesizes the latest updates in cytogenetic and molecular classifications, emphasizing the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) revisions. Key chromosomal alterations such as BCR::ABL1 and ETV6::RUNX1 and emerging subtypes including Ph-like ALL, DUX4, and MEF2D rearrangements are examined for their prognostic significance. Furthermore, we assess novel diagnostic tools, notably next-generation sequencing (NGS) and optical genome mapping (OGM). While NGS excels at identifying point mutations and small indels, OGM offers high-resolution structural variant detection with 100% sensitivity in multiple validation studies. These advancements enhance our grasp of leukemogenesis and pave the way for precision medicine in both B- and T-cell ALL. Ultimately, integrating these innovations into routine diagnostics is crucial for personalized patient management and improving clinical outcomes. Full article

To deliver the most effective cancer treatment, clinicians require rapid and accurate diagnoses that delineate tumor type, stage, and prognosis. Consequently, minimizing the need for repetitive and invasive procedures like biopsies and myelograms, along with their associated risks, is a critical challenge. Non-invasive monitoring offers a promising avenue for tumor detection, screening, and prognostication. While the identification of oncogenes and biomarkers from circulating tumor cells or tissue biopsies is currently standard practice for cancer diagnosis and classification, accumulating evidence underscores the significant role of epigenetics in regulating stem cell fate, including proliferation, self-renewal, and malignant transformation. This highlights the importance of analyzing the methylome, exosomes, and circulating RNA for detecting cellular transformation. The development of diagnostic assays that integrate liquid biopsies with epigenetic analysis holds immense potential for revolutionizing tumor management by enabling rapid, non-invasive diagnosis, real-time monitoring, and personalized treatment decisions. This review covers current studies exploring the use of epigenetic regulation, specifically the methylome and circulating RNA, as diagnostic tools derived from liquid biopsies. This approach shows promise in facilitating the differentiation between primary central nervous system lymphoma and other central nervous system tumors and may enable the detection and monitoring of acute myeloid/lymphoid leukemia. We also discuss the current limitations hindering the rapid clinical translation of these technologies. Full article

Background: Many risk factors for cancer therapy-related cardiovascular toxicity overlap with risk factors for atherosclerosis. According to the ESC 2022 Cardio-Oncology Guidelines, coronary computed tomography angiography and coronary artery calcium score are not recommended as part of routine risk assessment prior to oncological treatment. The aim of this study was to prospectively assess the influence of coronary artery calcium score (CAC score) on cancer therapy-related cardiac dysfunction in patients with moderate and high risk of cardiovascular toxicity, qualified for anthracycline treatment. Methods: In all patients, risk factors were collected, laboratory tests, echocardiography with global longitudinal strain (GLS) assessment and coronary artery tomography with coronary artery calcium score were performed. A total of 80 patients were included in the study, of which 77 (96.25%) were followed for an average of 11.5 months. The mean age at baseline was 60.5 years and 72 (93.51%) were women. Results: During observation, five patients (6.49%) died, including two due to heart failure and three due to cancer progression. The majority of patients (59, 76.6%) had breast cancer, 11 (14.3%) were diagnosed with sarcoma and seven (9.1%) with lymphoma. According to the HFA-ICOS risk score, 40 patients (51.9%) were classified as moderate risk (MR), and 37 patients (48.1%) as high risk (HR) for cancer therapy-related cardiovascular toxicity. A CAC score greater than 100 was calculated in 17 (22.1%) patients and greater than 400 in three (3.9%) patients. The CAC score above zero was more common in older patients and in patients classified as high risk (p < 0.001). There was also a significant association between CAC score and hypertension, hyperlipidemia, chronic kidney disease, and the level of NT-proBNP. During 12-month follow-up, mild CTRCD occurred in 38 (49.4%) patients, moderate CTRCD was diagnosed in seven (9.1%), and severe in three (3.9%) patients. In the univariable analysis, CTRCD was more common in the high-risk group (p = 0.005) and in patients with a CAC score greater than zero (p = 0.036). In multivariable analysis, the incidence of CTRCD remains higher in the CAC score > 0 group, even after adjusting for age, hypertension, and hyperlipidemia. In this study group, the CTRCD rates increased with the HFA-ICOS risk score. Conclusions: In moderate and high-risk patients, a coronary artery calcium score greater than zero was identified as a significant risk factor for the development of cancer therapy-related cardiac dysfunction during anthracycline-based treatment. Furthermore, the HFA-ICOS risk score demonstrated good correlation with the incidence of CTRCD in this study, supporting its validity as a predictive tool in patients receiving anthracycline therapy. Full article