Search Results (946)

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a block of differentiation and uncontrolled expansion of myeloid progenitor cells. Standard treatment includes intensive induction chemotherapy, typically with cytarabine and anthracycline, followed by consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation. However, these approaches are often associated with relapse and treatment-related toxicity. Accumulating evidence highlights a critical role for epigenetic dysregulation in driving disease initiation, progression, and therapeutic resistance. In this review, we examine an integrated framework of epigenetic regulation in AML, encompassing DNA methylation, histone post-translational modifications, chromatin remodeling, and RNA-mediated epigenetics. We discuss how alterations in key epigenetic regulators, such as DNMT3A, TET2, IDH1/2, EZH2, and histone-modifying enzymes, reshape the transcriptional and epigenetic landscape of leukemic cells. Particular emphasis is placed on epigenetically defined AML subtypes, including NPM1-mutated, DNMT3A-mutated, and KMT2A-rearranged AML, which illustrate distinct mechanisms of transcriptional and epigenetic dysregulation and confer unique therapeutic vulnerabilities. We further summarize current and emerging therapeutic strategies, ranging from conventional chemotherapy to molecularly targeted agents, epigenetic drugs, and immunotherapeutic approaches. Despite these advances, durable responses remain limited, highlighting the need to better understand epigenetic mechanisms to overcome resistance and improve patient outcomes. Full article

Background: As hyperbaric oxygen therapy has been sporadically used in combination with antimicrobial treatment for refractory infections in patients with hematologic malignancies, data on its efficacy and outcomes are limited. Methods: We retrospectively analyzed 55 patients with hematologic malignancies treated with hyperbaric oxygen therapy over a 10-year period at a single tertiary care center and report on patients’ clinical features, infection types, treatment responses, and survival outcomes. Results: The most common underlying hematologic malignancy diagnosis was acute myeloid leukemia (30 patients, 55%). The most common hyperbaric oxygen therapy indications were invasive mold disease (IMD) (35 patients, 64%), BK virus-associated cystitis (17 patients, 31%), and bacterial cellulitis (3 patients, 5%). Patients underwent a median of 10 hyperbaric oxygen therapy sessions (range, 1–45). In total, 54 (98%) of the 55 patients were evaluable for response, of whom 32 (59%) patients demonstrated a response, defined as either resolution or stabilization of the infection. Among the 35 patients with IMDs, we found that 11 patients (31%) achieved a complete response, 5 (14%) had a partial response, 6 (17%) had stable disease, and 13 (37%) patients experienced progression of their infection. In contrast, among the 17 patients with BK virus-associated cystitis, 9 patients (53%) had persistent or worsening hematuria. The two evaluable patients with bacterial cellulitis responded with resolution of the infection. We reviewed the status of the hematologic malignancies at the time of hyperbaric oxygen therapy treatment and found that the 21 patients whose hematologic malignancies were in remission tended to have a higher response rate of their infection compared to patients whose hematologic malignancies were not in remission (73% vs. 46% p = 0.057). Despite the response of infections, 1-year mortality in these patients remained high at 76%. Conclusions: Based on our experience, hyperbaric oxygen therapy, in conjunction with appropriate anti-infective therapy and debridement surgery, could benefit selected patients with hematologic malignancies, especially those whose underlying disease is controlled but experience recalcitrant bacterial or fungal infections. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Acute myeloid leukemia (AML) is one of the most common types of hematological malignancies and a leading cause of cancer deaths. It is characterized by the rapid accumulation of typically immature myeloid cells that serve to disrupt the production of mature cells, leading to a range of clinical sequelae. The role of recurrent chromosomal aberrations has long been appreciated in this disease, but a myriad of gene mutations have been increasingly acknowledged as having important roles. This review provides a comprehensive overview of the mutational landscape of AML, discussing the various genetic lesions in terms of their function, classification, etiological role, prognostic value, therapeutic impact, detection, and monitoring, with a particular focus on gene mutations. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Immunosenescence is a critical driver of tumor initiation and progression. In this study, we systematically characterized immune cell senescence by integrating transcriptomic profiles from 17 physiologically aged tissues with pan-cancer single-cell datasets, encompassing 206 samples across nine cancer types. Cross-tissue comparison of senescence-associated alterations, integrated with spatial transcriptomics, revealed that malignant cells triggered senescence in the core myeloid subpopulation designated Mac_DAB2 via a conserved MIF-CD74 signaling axis. By integrating shared myeloid differentiation programs across normal tissues and the tumor microenvironment (TME) with their transcriptional regulatory networks, we defined a myeloid senescence-associated gene (MSAG) signature. This signature successfully distinguishes a senescence-associated, immunosuppressive subtype linked to poor prognosis in pan-cancer cohorts. Finally, we established the MSAG.SIG prognostic model using an ensemble framework of 117 machine learning algorithms, which demonstrated robust and consistent predictive performance across multiple independent cohorts. Overall, this study elucidates the mechanisms underlying TME-driven myeloid senescence, establishes MSAG as a conceptual framework for characterizing myeloid immunosenescence, and provides a clinically relevant pan-cancer prognostic tool with translational potential. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC. Full article

Membranous nephropathy (MN) and minimal change disease (MCD) are the most common causes of nephrotic syndrome following hematopoietic stem cell transplantation (HSCT), a complication conventionally attributed to chronic graft-versus-host disease (GVHD). Paraneoplastic MCD is well described in lymphoid malignancies but is rarely reported in myeloid neoplasms. We report two cases of biopsy-confirmed MCD presenting as the initial manifestation of acute myeloid leukemia (AML) relapse following allogeneic HSCT. Both patients were White men in their sixties with relapsed/refractory AML who developed nephrotic-range proteinuria and acute kidney injury after matched unrelated donor HSCT without histologic evidence of GVHD. Renal biopsies confirmed MCD in both cases. Corticosteroid therapy was ineffective in halting renal deterioration; renal function improved only after initiation of leukemia-directed therapy, with one patient achieving dialysis independence. These cases highlight a rare paraneoplastic presentation of AML relapse. Nephrotic syndrome due to MCD may signal post-HSCT leukemia recurrence, and evaluation for AML relapse warrants consideration in steroid-refractory cases or those without concurrent GVHD. In such cases, control of the underlying malignancy, rather than escalation of immunosuppression, may be central to renal recovery. Full article

Acute myeloid leukemia (AML) is a biologically heterogeneous malignancy in which therapeutic decision-making is increasingly guided by molecular and immunophenotypic diagnostics. Advances in genomic profiling and risk stratification have enabled the integration of targeted agents into frontline and relapsed/refractory treatment strategies. Among these, midostaurin, venetoclax, and gemtuzumab ozogamicin represent paradigm-shifting therapies whose clinical benefit depends on accurate and timely diagnosis. This review examines the diagnostic frameworks that inform the use of these agents and discusses their incorporation into contemporary AML management. Midostaurin has demonstrated improved outcomes in patients with FLT3-mutated AML when combined with intensive chemotherapy, underscoring the importance of early molecular testing. Venetoclax, a BCL-2 inhibitor, has expanded therapeutic options for older or unfit patients when used with hypomethylating agents or low-dose cytarabine, with emerging evidence linking response to cytogenetic and molecular features. Gemtuzumab ozogamicin, an anti-CD33 antibody–drug conjugate, illustrates the clinical relevance of immunophenotypic assessment and risk-adapted dosing strategies. We highlight current evidence supporting diagnosis-driven therapy selection, practical considerations for clinical implementation, and ongoing challenges, including resistance mechanisms and optimal sequencing. Integrating precise diagnostic tools with targeted therapies represents a critical step toward personalized AML care and improved patient outcomes. Full article

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Myeloid-derived suppressor cells (MDSCs) are a class of immature, heterogenous, and functionally immunosuppressive myeloid progenitors that are expanded in malignant disease including glioblastoma (GBM). Extensive preclinical evaluation of GBM has revealed that MDSCs express multiple different chemokine and cytokine receptors that facilitate their entry, infiltration, expansion and immunosuppression of antitumor immunity in the tumor microenvironment. Additionally, translational investigation of approaches that target MDSCs directly or indirectly through immune remodeling has yielded promising effects that are under clinical trial investigation. Given the immunosuppressive phenotype of high-grade gliomas like GBM, the removal of MDSCs represents a clinically relevant strategy to enhance immune responses against neoplastic cells. In this review, we provide a comprehensive summary of MDSCs in GBM, emphasizing clinical observations and large-scale multi-omics studies that position MDSCs at the nexus of GBM immunosuppression. Next, we provide detailed coverage of multiple chemokines, cytokines, and growth factors that are relevant to MDSC migration, survival and expansion in GBM along with commentary on the associated receptors. Lastly, we discuss therapeutic approaches that directly target MDSCs as a strategy to improve immune responses against malignant brains and observations on the changes to MDSCs in the tumor microenvironment after immunotherapy. Our review serves as a valuable resource for the neuro-oncology research space, updating scientists and clinicians on a cell central to the biology and therapeutic targeting of GBM. Full article

Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes in relapsed or refractory hematologic malignancies, but long-term cognitive outcomes remain poorly understood. We compared the incidence and time course of cognitive impairment and associated neurological complications after CAR-T therapy compared with autologous stem cell transplantation (ASCT). Methods: This retrospective, propensity-matched cohort study utilized the TriNetX US Collaborative Network (January 2014–April 2025). To ensure concurrent comparisons, ASCT recipients were restricted to an index date beginning in August 2017 or later. CAR-T recipients were matched 1:1 to ASCT recipients for demographics, disease, comorbidities, prior and concomitant treatments, and laboratory parameters. The primary endpoint was time to cognitive impairment, as defined by ICD-10 codes. Results: After comparing 3067 CAR-T patients (median follow-up 634 days) with 3067 ASCT patients (median follow-up 713 days), CAR-T recipients had a higher risk of cognitive impairment (HR 1.58; 95% CI 1.39–1.80; p < 0.001). Because the risks were not proportional (Schaenfeld p < 0.001), the difference was also expressed as restricted median survival time (RMST): CAR-T recipients spent approximately 25 and 53 days fewer days without cognitive impairment at 1 and 2 years, respectively (both p < 0.001). The risk was greatest at 30 days (HR 4.22; 95% CI 3.23–5.53), but remained elevated in control analyses at 30 and 90 days that excluded the acute ICANS window (HR 1.30 and 1.25, respectively; both p < 0.05). Neurological dysfunction, particularly encephalopathy (HR 2.04; 95% CI 1.73–2.40), was more common after CAR-T. Conversely, CAR-T was associated with a reduced risk of secondary acute myeloid leukemia (HR 0.46; 95% CI 0.38–0.55; p < 0.001). Conclusions: CAR-T therapy is associated with a higher risk of cognitive impairment that persists beyond the acute phase. As these are observational, code-based data, they should be interpreted as associations rather than evidence of a specific mechanism, and they highlight the need for informed consent discussions, long-term neurocognitive monitoring, and the development of neuroprotective strategies. Full article

Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF). Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress. This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development. Full article

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous hematologic malignancy in which intensive induction chemotherapy remains the standard therapeutic platform for medically fit adults. In recent years, however, the frontline treatment paradigm has progressively evolved from a purely cytotoxic approach toward a biologically informed strategy. This shift has been driven by the identification of recurrent molecular alterations—particularly FLT3 and IDH1/2 mutations—as well as renewed interest in antibody-based therapies and the growing recognition that relapse, resistance, and measurable residual disease (MRD) are shaped by clonal architecture rather than blast burden alone. This review examines the development of targeted therapies combined with intensive chemotherapy in AML. We discuss the biological rationale for combination approaches and summarize the key clinical studies that have defined current practice, including trials evaluating FLT3 inhibitors, gemtuzumab ozogamicin, IDH inhibitors, and venetoclax-based strategies. We also address the role of targeted therapy across different treatment phases, including induction, consolidation, and post-remission settings, and analyze emerging data regarding MRD-guided treatment strategies, mechanisms of resistance, and integration with allogeneic hematopoietic stem cell transplantation. The integration of targeted agents with intensive chemotherapy is reshaping frontline AML therapy and represents a critical step toward precision medicine. While genotype-directed strategies—such as FLT3 inhibition—have already demonstrated survival benefit, optimal patient selection, treatment sequencing, and duration remain areas of active investigation. Future progress will likely depend on MRD-driven treatment adaptation, improved understanding of clonal evolution, and the development of rational multi-agent combinations capable of achieving deeper and more durable remissions. Full article