Search Results (47)

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) 4 alone or in combination with other drugs, has led to unexpected positive results in some tumors but not all. Several other molecules inhibiting lymphocyte antitumor effector subsets have been discovered in the last 30 years. Herein, we focus on the leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1/CD305). LAIR1 represents a typical immunoregulatory molecule expressed on almost all leukocytes, unlike other regulatory receptors expressed on discrete leukocyte subsets. It bears two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the intracytoplasmic protein domain involved in the downregulation of signals mediated by activating receptors. LAIR1 binds to several ligands, such as collagen I and III, complement component 1Q, surfactant protein D, adiponectin, and repetitive interspersed families of polypeptides expressed by erythrocytes infected with Plasmodium malariae. This would suggest LAIR1 involvement in several cell-to-cell interactions and possibly in metabolic regulation. The presence of both cellular and soluble forms of LAIR would indicate a fine regulation of the immunoregulatory activity, as happens for the soluble/exosome-associated forms of PD1 and CTLA4 molecules. As a consequence, LAIR1 appears to play a role in some autoimmune diseases and the immune response against tumor cells. The finding of LAIR1 expression on hematological malignancies, but also on some solid tumors, could open a rationale for the targeting of this molecule to treat neoplasia, either alone or in combination with other therapeutic options. Full article

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

Clonal hematopoiesis (CH) is an age-related process in which hematopoietic stem/progenitor cells increase their fitness due to the acquisition of mutations that lead to a proliferative advantage and to clonal expansion. Its frequency increases with age, and it mostly affects people older than 70 years. The most mutated genes in CH are epigenetic regulators, DNA damage response genes, and splicing factors, which are all involved in the development of myeloid neoplasia. Some risk factors, including age, smoking, and prior cytotoxic therapy, increase the risk of developing CH or increase the fitness of CH. Various types of CH have been observed, associated or not with cytopenias or monocytosis. CH represents a risk factor for many pathological conditions and particularly for hematologic malignancies. A better understanding of the risks related to CH has triggered the development of research, translational, and clinical programs for the monitoring, prevention, and treatment of CH. Full article

Background: Cervical cancer, primarily driven by persistent high-risk human papillomavirus (HPV) infections, remains a significant global health challenge. Systemic inflammatory markers, such as neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR), may reflect disease progression. This study examines the association between these markers and p16 positivity in cervical intraepithelial neoplasia (CIN) cases. Methods: This retrospective analysis included 395 patients undergoing LEEP conization. Data on HPV status, p16 immunostaining, and hematological parameters were collected. Statistical analyses, including Mann–Whitney U and chi-square tests, assessed relationships between markers and outcomes, with significance set at p < 0.05. Results: Elevated NLR was significantly associated with p16 positivity (p = 0.011) and HPV DNA positivity (p = 0.04). HPV-positive individuals showed higher mean NLR (2.15) compared to HPV-negative individuals (1.61). Receiver operating characteristic (ROC) analysis demonstrated moderate diagnostic accuracy for NLR (AUC = 0.610), highlighting its potential as a biomarker. No significant associations were observed for PLR or LMR with p16 positivity. These findings suggest systemic inflammation, indicated by NLR, contributes to HPV persistence and CIN progression. Conclusions: NLR is a valuable prognostic biomarker for HPV-related cervical disease, correlating with both p16 and HPV DNA positivity. Incorporating hematological and immunohistochemical markers may enhance personalized cervical cancer management. Full article

Despite the advances of CAR-T cells in certain hematological malignancies, mostly from B-cell derivations such as non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, a significant portion of other hematological and non-hematological pathologies can benefit from this innovative treatment, as the results of clinical studies are demonstrating. The clinical application of CAR-T in the setting of acute T-lymphoid leukemia, acute myeloid leukemia, solid tumors, autoimmune diseases and infections has encountered limitations that are different from those of hematological B-cell diseases. To overcome these restrictions, strategies based on different molecular engineering platforms have been devised and will be illustrated below. The aim of this manuscript is to provide an overview of the CAR-T application in pathologies other than those currently treated, highlighting both the limits and results obtained with these settings. Full article

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the accumulation of abnormal plasma cells in the bone marrow. Mesenchymal stem cells (MSCs) and reticulated platelets (RPs) have been implicated in the pathogenesis of MM. This narrative review aims to explore the role of MSCs and RPs in the pathophysiology of MM, particularly their clinical use as possible variables of prognostic value in this hematologic neoplasia. The interaction between MSCs and MM cells within the bone marrow microenvironment supports MM cell survival, proliferation, and drug resistance. MSCs contribute to the development and maintenance of MM through the secretion of various factors, including cytokines, chemokines, and growth factors. Moreover, RPs, young and highly reactive platelets, have been implicated in promoting angiogenesis, tumor growth, and metastasis in MM. Several studies show that cells such as MSCs and platelets participate actively in the biology of the disease. Still, in clinical practice, they are not considered part of evaluating affected patients. In this review, we explore the possibility of including the evaluation of MSCs and PRs in the clinical practice for patients with MM as part of the strategies to improve the outcomes of this disease. Full article

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasia with a complex polyclonal architecture. Among driver lesions, those involving the FLT3 gene represent the most frequent mutations identified at diagnosis. The development of tyrosine kinase inhibitors (TKIs) has improved the clinical outcomes of FLT3-mutated patients (Pt). However, overcoming resistance to these drugs remains a challenge. To unravel the molecular mechanisms underlying therapy resistance and clonal selection, we conducted a longitudinal analysis using a single-cell DNA sequencing approach (MissionBioTapestri® platform, San Francisco, CA, USA) in two patients with FLT3-mutated AML. To this end, samples were collected at the time of diagnosis, during TKI therapy, and at relapse or complete remission. For Pt #1, disease resistance was associated with clonal expansion of minor clones, and 2nd line TKI therapy with gilteritinib provided a proliferative advantage to the clones carrying NRAS and KIT mutations, thereby responsible for relapse. In Pt #2, clonal architecture was less complex, and 1st line TKI therapy with midostaurin was able to eradicate the leukemic clones. Our results corroborate previous findings about clonal selection driven by TKIs, highlighting the importance of a deeper characterization of individual clonal architectures for choosing the best treatment plan for personalized approaches aimed at optimizing outcomes. Full article

The occurrence of second primary malignancies is becoming increasingly important among cancer survivors. Melanoma, an aggressive neoplasm originating from the melanocytes, is responsible for most skin cancer-related deaths. This review aims to explore the risk of melanoma occurrence as a second primary cancer after the most common subtypes of hematologic neoplasia, a malignant disease originating from myeloid or lymphocytic cell lineages. Chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are among the most associated subtypes with melanoma development. We also discuss the underlying hypotheses that may explain the associations between these malignancies and the impact of melanoma on survival. The review emphasizes the importance of increasing awareness of melanoma risk in hematologic cancer survivors, as it can lead to prompt recognition, improved skin surveillance, and better survival outcomes. Full article

Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation. Full article

Although advances in the management of pediatric neoplasms have profoundly improved infectious disease outcomes, invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in children and adolescents with high-risk hematological malignancies. A retrospective study was conducted in the Pediatric Hematology–Oncology Department of the University General Hospital of Heraklion for 2013–2022 to estimate the prevalence and describe the clinical and epidemiological characteristics of IFDs for pediatric and adolescent patients with neoplasia. Demographic, clinical, and laboratory parameters were analyzed to identify risk factors for the development of IFD. The overall prevalence of IFDs was estimated to be 7.8% (12/154 patients) throughout the study. The mean age at IFD diagnosis was 9.8 years (SD 6.4 years). The most common IFD was possible/probable invasive pulmonary aspergillosis (IPA; in ≈50%), followed by candidemia/invasive candidiasis (in 44%). Candida parapsilosis was the most prevalent Candida species (4/6 events). Of interest, the majority (75%) of IFDs were breakthrough infections. Patients with increased risk for IFDs were those who were colonized by fungi in sites other than the oral cavity, hospitalized in the intensive care unit for >7 days, received >7 different antimicrobials in the last 3 months, or had severe neutropenia for >44 days. Two children out of a total of 12 with IFD died due to refractory disease or relapse (16.7%). More detailed and prospective epidemiological studies on fungal infections in pediatric patients with hematological or solid neoplasms can contribute to the optimization of prevention and treatment. Full article

Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets. Full article

The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat’s therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects. Full article

Background: Artificial intelligence in medicine is a field that is rapidly evolving. Machine learning and deep learning are used to improve disease identification and diagnosis, personalize disease treatment, analyze medical images, evaluate clinical trials, and speed drug development. Methods: First, relevant aspects of AI are revised in a comprehensive manner, including the classification of hematopoietic neoplasms, types of AI, applications in medicine and hematological neoplasia, generative pre-trained transformers (GPTs), and the architecture and interpretation of feedforward neural net-works (multilayer perceptron). Second, a series of 233 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-CHOP from the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) was analyzed. Results: Using conventional statistics, the high expression of MYC and BCL2 was associated with poor survival, but high BCL6 was associated with a favorable overall survival of the patients. Then, a neural network predicted MYC, BCL2, and BCL6 with high accuracy using a pan-cancer panel of 758 genes of immuno-oncology and translational research that includes clinically relevant actionable genes and pathways. A comparable analysis was performed using gene set enrichment analysis (GSEA). Conclusions: The mathematical way in which neural networks reach conclusions has been considered a black box, but a careful understanding and evaluation of the architectural design allows us to interpret the results logically. In diffuse large B-cell lymphoma, neural networks are a plausible data analysis approach. Full article

Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies. Full article