Experimental Hematology & Oncology最新文献

Breast cancer remains one of the most prevalent malignancies worldwide, underscoring an urgent need for innovative therapeutic strategies. Immunotherapy has emerged as a transformative frontier in this context. In triple-negative breast cancer (TNBC), the combination of immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with chemotherapy has proven efficacious in both early and advanced clinical trials. These encouraging results have led to the approval of ICIs for TNBC, opening up new therapeutic avenues for challenging-to-treat patient populations. Furthermore, a multitude of ongoing trials are actively investigating the efficacy of immunotherapy-based combinations, including ICIs in conjunction with chemotherapy, targeted therapy and radiation therapy, as well as other novel strategies such as bispecific antibodies, CAR-T cells and cancer vaccines across all breast cancer subtypes, including HR-positive/HER2-negative and HER2-positive disease. This review provides a comprehensive overview of current immunotherapeutic approaches in breast cancer, highlighting pivotal findings from recent clinical trials and the potential impact of these advancements on patient outcomes.

Nanotechnology has revolutionized cancer therapy by introducing advanced drug delivery systems that enhance therapeutic efficacy while reducing adverse effects. By leveraging various nanoparticle platforms-including liposomes, polymeric nanoparticles, and inorganic nanoparticles-researchers have improved drug solubility, stability, and bioavailability. Additionally, new nanodevices are being engineered to respond to specific physiological conditions like temperature and pH variations, enabling controlled drug release and optimizing therapeutic outcomes. Beyond drug delivery, nanotechnology plays a crucial role in the theranostic field due to the functionalization of specific materials that combine tumor detection and targeted treatment features. This review analyzes the clinical impact of nanotechnology, spanning from early-phase trials to pivotal phase 3 studies that have obtained regulatory approval, while also offering a critical perspective on the preclinical domain and its translational potential for future human applications. Despite significant progress, greater attention must be placed on key challenges, such as biocompatibility barriers and the lack of regulatory standardization, to ensure the successful translation of nanomedicine into routine clinical practice.

Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.

Background: Neutropenic enterocolitis (NE) is a severe digestive complication of chemotherapy, primarily affecting patients with acute myeloid leukemia (AML). We hypothesized that NE is linked to intestinal barrier dysfunction and gut dysbiosis.

Methods: Sixty-five AML patients undergoing induction chemotherapy were included in this prospective monocentric cohort. Among them, 26 patients (40%) were diagnosed with NE. Stool samples were subjected to bacterial load quantification (all bacteria quantitative PCR), 16s rRNA metagenomic analysis, and short-chain-fatty-acids quantification. Additionally, fecal calprotectin and human 𝛃-defensin 2 along with plasmatic inflammatory cytokines, and citrulline levels were measured. Human transcriptomic analysis was conducted on samples obtained from anatomical specimens of colectomies of NE patients.

Results: Gut microbiota underwent significant alterations after chemotherapy, transitioning from a diverse and balanced enterotype to enterotypes exhibiting a reduced α-diversity, an increased abundance of Enterococcus faecalis, and a decreased abundance of butyrate-producing genera, which correlated with a decreased fecal concentration of butyrate. Simultaneously, post-chemotherapy, plasma citrulline concentrations decreased indicating enterocyte damages. Finally, human transcriptomic analysis found a significant upregulation of the JAK-STAT signaling KEGG pathway in the colons of NE patients encompassing cytokines (IL-6, OSM-OSMR) that play a pivotal role in sustaining local inflammation within the digestive tract.

Conclusions: This work reaffirms the significant influence of chemotherapy on the gut microbiota and the integrity of the enterocyte barrier. Severe NE is marked by the development of a local inflammatory response that may be induced by the reduction in butyrate levels.

Trial registration: The study was registered on Clinicaltrials.gov (identifier: NCT04438278).

Over 90% of patients with myelodysplastic syndromes/neoplasms (MDS) exhibit anemia at diagnosis, primarily due to ineffective erythropoiesis. This is characterized by abnormal proliferation and differentiation of erythroid cells influenced by signaling pathways including heme synthesis, ferroptosis, senescence and apoptosis. Despite widespread anemia, the specific mechanisms and pathway alterations at different disease stages are not well understood. This study employed the NUP98-HOXD13 (NHD13) transgenic mouse model, which mimicked the erythroid changes observed in MDS patients, to explore these dynamic pathway changes during disease progression. Based on the severity of anemia and changes in mean corpuscular volume (MCV), four time points were selected: 6 weeks (non-anemic), 12 weeks (mild anemia), 16 weeks (obvious anemia) and 20 weeks (severe macrocytic anemia). The findings indicated that a reduction in erythroid-committed progenitors and impaired erythroid maturation were linked to ineffective erythropoiesis. As the disease progressed, signaling pathways dynamically changed. Heme metabolism and ferroptosis pathways were significantly upregulated in the pre-disease and early disease stages, while senescence and cell cycle pathways were activated in the early stage. The prominent roles of apoptosis, pyroptosis and inflammasome signaling pathways were observed in the late stage. Notably, changes in Gpx4 and Ncoa4 expression, along with transmission electron microscopy analysis, suggested that ferroptosis played a critical role in the early stage of the disease. To our knowledge, this is the first report of the signaling pathway dynamics associated with ineffective erythropoiesis during the pathogenesis and progression of MDS, highlighting potential targets for therapeutic intervention at various stages of the disease.

Sarcomas are rare, heterogeneous mesenchymal malignancies with notably high misdiagnosis rates. Despite sarcoma patients in China representing about one-quarter of the global disease burden, large-scale NGS-based diagnostic studies remain scarce, with limited sample sizes failing to capture the extensive subtype complexity of sarcomas. To address diagnostic gaps, we conducted the largest multicenter study in China involving 788 patients with soft tissue or bone sarcomas. All samples underwent targeted RNA sequencing (Fusioncapture) alongside standard histopathology, immunohistochemistry, and DNA-based next-generation sequencing (NGS). Compared with DNA-NGS, RNA-based profiling clarified ambiguous fusion calls and uncovered numerous additional and clinically relevant events, including 281 fusions not captured by the DNA panel. Notably, 114 recurrent alterations were strongly subtype-associated, and 20 newly identified receptor tyrosine kinase fusions had therapeutic significance, expanding targetable cases from 3.3% to 6.5%. Furthermore, integrated RNA data led to subtype reclassification in 11.9% of patients, including 22% of those initially diagnosed as "not otherwise specified". These findings confirm the utility of targeted RNA sequencing for detecting transcriptionally active fusions, refining pathological classifications, and identifying actionable variants in Chinese sarcoma patients. Despite retrospective design and limited orthogonal validation of some fusions, our results strongly support incorporating RNA-based assays into routine clinical workflows. Ultimately, this integrated approach can improve diagnostic precision, guide personalized treatment strategies, and enhance outcomes for sarcoma patients.

Letermovir is an antiviral agent that significantly decreases the frequency of cytomegalovirus (CMV) infections following allogeneic hematopoietic stem cell transplantation (allo-HCT); however, its impact on Epstein-Barr virus (EBV) infection remains unclear. This multicenter, retrospective study involved 565 patients aged ≥ 18 years, who underwent allo-HCT between January 2021 and December 2023, with 284 receiving letermovir prophylaxis (letermovir group) and 281 not (control group). Cumulative incidences of clinically significant CMV infection (cs-CMVi), EBV DNAemia, EBV-disease and post-transplant lymphoproliferative disorder (PTLD) were compared between the groups. The 1-year cumulative incidence of EBV DNAemia did not differ significantly between the letermovir and control groups (58.1% vs. 52.7%, P = 0.3). However, letermovir prophylaxis was associated with a significantly higher incidence of PTLD within the first year post-HCT (7.39% vs. 1.80%, P = 0.00059). Multivariate analysis identified letermovir prophylaxis as an independent risk factor for PTLD (HR [95% CI]: 4.619 [1.458-10.278], P = 0.007). Letermovir altered the early reconstitution trajectory after allo-HCT, particularly in CD8⁺ T cells. Our findings emphasized that although letermovir prophylaxis did not increase the risk of EBV DNAemia in allo-HCT recipients, it was associated with a higher incidence of PTLD. Further studies focusing on immune reconstitutiom dynamics are warranted to elucidate the underlying pathophysiology of EBV-PTLD under letermovir pressure.

Diagnosis-to-treatment interval (DTI) is an important prognostic factor in patients with newly diagnosed aggressive lymphomas, however the impact of DTI on outcomes in marginal zone lymphoma (MZL) is unknown. In this multicenter retrospective cohort study, we included adult patients with MZL who received first-line immunochemotherapy within 120 days of diagnosis at 10 US medical centers. Patients who received treatment within 60 days from their diagnosis were classified into the short DTI group and those who received treatment beyond 60 days into long DTI group. The primary objective was progression-free survival (PFS), while secondary objectives included overall survival (OS) and cumulative incidence of histologic transformation (HT) between the two groups. Of the 870 patients with newly diagnosed MZL, 177 patients met the inclusion criteria and were included in this analysis. Among these 144 (81%) were in the short DTI group and 33 (19%) in the long DTI group. In the univariable analysis, presence of B symptoms was associated with short DTI and remained significantly associated with short DTI in the multivariable analysis (OR = 11.91, p = 0.017). Short DTI was not associated with a statistically different PFS or OS compared to long DTI in the univariable or in multivariable analysis. The cumulative incidence of HT was not significantly different between the two groups. This is the first study to-date to report on the association of DTI on outcomes in MZL patients. This lack of prognostic utility of DTI in newly diagnosed MZL, in contrast to aggressive B-cell lymphomas, may be intrinsically linked to the underlying disease biology.

Haematological malignancies are one of the most common tumors, with a rising incidence noted over recent decades. Viral infections play significant roles in the pathogenesis of these malignancies globally. This review delves into the contributions of various known viruses-specifically Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), human T-cell leukemia virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV), hepatitis B virus (HBV), hepatitis C virus (HCV), and human papillomavirus (HPV)-in the development of haematological malignancies. These viruses are shown to drive tumorigenesis through mechanisms, such as metabolic reprogramming, epigenetic modifications, and remodeling of the immune microenvironment. By directly disrupting fundamental cellular functions and altering metabolic and epigenetic pathways, these viruses foster an immune milieu that supports both viral persistence and tumor growth. A thorough understanding of these viral oncogenic processes is crucial not only for etiological discovery but also for developing targeted interventions. This review emphasizes the need for continued research into the specific ways these viruses manipulate the host cell's metabolic and epigenetic environments, aiming to provide insights that could guide future advancements in treatment modalities.

Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.