Search Results (133)

Hibiscus sabdariffa (Hs) is a tropical plant with a wide range of therapeutic properties; however, few studies have evaluated its potential adverse effects. In the present study, the cytotoxic and genotoxic effects of the hydroalcoholic extract of Hs (EHHs) dried calyces administered during gestation were assessed in Wistar rats and their newborns using the micronucleus assay in peripheral blood and the quantification of malondialdehyde (MDA) in various tissues. Three different doses of EHHs (500, 1000, and 2000 mg/Kg) were administered orally to five pregnant Wistar rats per group during the final days of gestation (days 16–20). Blood samples were collected every 24 h during the last six days of gestation and from the neonates at birth, along with tissue samples for MDA quantification. EHHs induced myelosuppression in the mothers and genotoxicity in their newborns, as well as cytotoxicity, evidenced by increased MDA levels in serum, liver, and kidneys of the mothers, and in the liver, kidneys, brain, and muscle tissues of the neonates. These findings provide important insights into the safety profile of Hs, and its use is therefore recommended only under the supervision of a qualified healthcare professional. Full article

Poloxamer 188 is a polymer that is used as a carrier and stabilizer of pharmacological agents. It has been demonstrated to enhance red blood cell and hemoglobin levels in healthy animals and in select clinical cases. The objective of this study was to assess the efficacy of Poloxamer 188 in CBA mice when administered repeatedly in the carboplatin-induced myelosuppression model. The mice were administered carboplatin once at a dose of 100 mg/kg, and then Poloxamer 188 was orally administered daily at doses of 10 mg/kg, 100 mg/kg, 500 mg/kg, and 1000 mg/kg for 7 and 21 days. Poloxamer 188 at a dose of 1000 mg/kg was found to bring the level of 2,3-bisphosphoglycerate in red blood cells close to control level (p = 0.1331 for the control group compared to Poloxamer at a dose 1000 mg/kg) already from day 8 of the study and in bone marrow resulted in regulation of genes responsible for hematopoiesis. G-GSF at day 8 and TNFα at day 22 gene expression was significantly decreased by 54% (p = 0.012) and 16% (p = 0.024), respectively, with Poloxamer 188 administration at a dose of 100 mg/kg. Additionally, in the bone marrow, the treatment was seen to exert a positive regulatory effect on the genes responsible for hematopoiesis. These findings are consistent with the observed increase in red blood cell by 6.7% (p = 0.001), hemoglobin by 4.7% (p = 0.0053), and reticulocyte percentage by 53.6% (p < 0.0001) following Poloxamer 188 administration at a dose of 1000 mg/kg in CBA mice with myelosuppression. Full article

Background and Clinical Significance: Intermediate- to high-risk Myelodysplastic Syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-M), confers a high risk of progression into acute myeloid leukemia. Treatment with hypomethylating agents, including azacitidine and decitabine, represents the current standard of care. In eligible patients, hypomethylating agents are used as a bridge for allogeneic stem cell transplantation, currently the only curative approach in these malignancies. The most common side effects of hypomethylating agents are myelosuppression, cutaneous injection site reactions (when azacitidine is given subcutaneously), and gastrointestinal symptoms. Uncommon, disabling, and long-lasting side effects represent a threat to effective treatment in this group of patients. Case Presentation: We describe the case of a 49-year-old male patient with IPSS-M intermediate-risk MDS, intended to receive first-line treatment with azacitidine followed by allogeneic stem cell transplantation. The first, late-onset azacitidine reaction was observed 48 h after the first exposure, with cutaneous and respiratory toxicity, followed by the late-onset recurrence of symptoms after azacitidine withdrawal and decitabine introduction. Conclusions: This case highlights atypical, disabling, and long-lasting drug reactions to two hypomethylating agents, with the persistence of hypersensitivity manifestations months after medication withdrawal. Full article

Background: Patients with refractory and relapsed acute myeloid leukemia (R/R AML) face a dismal prognosis. CAR-T therapy has emerged as a potential treatment option. This study assesses the available clinical evidence on CAR-T in R/R AML, focusing on safety and efficacy outcomes. Methods: We included studies on CAR-T therapy for R/R AML published from June 2014 to January 2025. Data on patient and disease characteristics, CAR-T constructs, response rates, post-CAR-T allogeneic HSCT (allo-HSCT), and safety outcomes were analyzed. Results: Twenty-five CAR-T clinical trials involving 296 patients were identified. The most frequently targeted antigens were CD33, CD123, and CLL-1, while CD7, CD19, NKG2D, and CD38 were also explored. Responses were heterogeneous and often short-lived when not consolidated with allo-HSCT. Cytokine release syndrome and neurotoxicity were generally low grade and manageable. Prolonged and severe myelosuppression was a frequent limiting toxicity, often requiring allo-HSCT to restore hematopoiesis. Disease progression was the leading cause of death, followed by infections. Conclusions: CAR-T cell therapy may represent a feasible therapeutic strategy, particularly as bridging to allo-HSCT to mitigate myelotoxicity and improve long-term outcomes. Nevertheless, it remains in the early stages of development and faces significant efficacy and safety challenges that must be addressed in future trials to enable the expansion of this promising therapeutic approach for a population with high unmet medical needs. Full article

Background: High-dose γ-ray exposure (≥7 Gy) in nuclear emergencies induces life-threatening acute radiation syndrome, characterized by rapid hematopoietic collapse (leukocytes <0.5 × 10⁹/L) and gastrointestinal barrier failure. While clinical biomarkers like leukocyte depletion guide current therapies targeting myelosuppression, the concomitant metabolic disturbances and gut microbiota dysbiosis—critical determinants of delayed mortality—remain insufficiently profiled across the 28-day injury-recovery continuum. Methods: This study investigates the effects of ⁶⁰Co γ-ray irradiation on metabolic characteristics and gut microbiota in Sprague Dawley rats using untargeted metabolomics and 16S rRNA sequencing. Meanwhile, body weight and complete blood counts were measured. Results: Body weight exhibited significant fluctuations, with the most pronounced deviation observed at 14 days. Blood counts revealed a rapid decline in white blood cells, red blood cells, and platelets post-irradiation, reaching nadirs at 7–14 days, followed by gradual recovery to near-normal levels by 28 days. Untargeted metabolomics identified 32 upregulated and 33 downregulated plasma metabolites at 14 days post-irradiation, while fecal metabolites showed 47 upregulated and 18 downregulated species at 3 days. Key metabolic pathways impacted included Glycerophospholipid metabolism, alpha-linolenic acid metabolism, and biosynthesis of unsaturated fatty acids. Gut microbiota analysis demonstrated no significant change in α-diversity but significant β-diversity shifts (p < 0.05), indicating a marked alteration in the compositional structure of the intestinal microbial community following radiation exposure. Principal coordinate analysis confirmed distinct clustering between control and irradiated groups, with increased abundance of Bacteroidota and decreased Firmicutes in irradiated rats. These findings highlight dynamic metabolic and microbial disruptions post-irradiation, with recovery patterns suggesting a 28-day restoration cycle. Spearman’s rank correlation analysis explored associations between the top 20 fecal metabolites and 50 abundant bacterial taxa. Norank_f_Muribaculaceae, Prevotellaceae_UCG-001, and Bacteroides showed significant correlations with various radiation-altered metabolites, highlighting metabolite–microbiota relationships post-radiation. Conclusions: This study provides insights into potential biomarkers for radiation-induced physiological damage and underscores the interplay between systemic metabolism and gut microbiota in radiation response. Full article

Background/Objectives: The epigenetic drug 5-azacytidine (AzaC) is being used for the treatment of myeloproliferative diseases. It has multiple immunomodulating activities: it enhances the activity of Treg cells and suppresses effector T cell proliferation and function. Our aim was to repurpose AzaC for the treatment of multiple sclerosis (MS). AzaC treatment of myelodysplastic syndrome often improves the autoimmune disorders accompanying it. Another epigenetic drug, decytabin, was effective in EAE, suggesting that AzaC might behave similarly. Earlier, we found that AzaC improves aggrecan-induced arthritis in mice, further supporting our hypothesis. Methods: AzaC was tested in an animal model of MS: MOG_35–55-induced experimental allergic encephalomyelitis (EAE) in B6 mice. In addition to AzaC, its ester, prodrug triacetyl-5-azacytidine (TAC), reported earlier to exhibit improved stability and oral bioavailability, was also tested. Results: In our proof-of-concept experiment, i.p. administered AzaC ameliorated EAE. Then, we demonstrated that oral TAC is as effective as the positive comparator fingolimod. Next, we demonstrated that sub-optimal doses of oral TAC and fingolimod positively synergize. Importantly, the myelosuppression induced by TAC was not worse than that of the gold-standard fingolimod. Conclusions: Ours is the first study reporting the therapeutic activity of oral TAC. Both AzaC and TAC were effective in EAE; therefore, they can be proposed for the treatment of remitting–relapsing MS and possibly other autoimmune diseases. In addition, combination treatment with TAC and fingolimod might allow for lower individual drug doses, thus offering an alternative when side effects limit the use of current multiple sclerosis drugs. Full article

Background/Objectives: The blood–brain barrier and blood-CSF barrier limit the uptake of CNS-targeted therapeutics, warranting utilization of intra-cerebrospinal fluid (CSF) drug delivery. Here we review and compare the safety and distribution of different intra-CSF delivery methods reported in clinical literature. Methods: A retrospective literature review of three common CSF access methods was performed. A search consisting of clinical trials published on PubMed from 2000–2024 using the following search terms—intracerebroventricular/intraventricular/ICV, intrathecal/IT, intralumbar/lumbar puncture, cisterna magna/ICM/IT-CM, drug delivery, drug administration, and CSF—yielded 38 intracerebroventricular (ICV), 110 lumbar intrathecal (LIT), and six intra-cisterna magna (ICM) studies. Results: After final exclusion criteria were applied, there were 12 ICV, two LIT, and zero ICM publications remaining for analysis. ICV-specific safety was addressed in 11 ICV publications, with headache, nausea, and vomiting being among the most frequently mentioned procedure-associated adverse events (AEs). LIT-specific safety was provided in only one of the two studies, reporting mostly grade 1/2 AEs but also an instance of grade 4 myelosuppression. For clinical efficacy, progression-free survival (PFS), overall survival (OS), and disease progression rates were largely variable across studies. Pharmacokinetics were analyzed in four ICV studies. Conclusions: The safety profiles of both ICV and LIT injections are acceptable, showing mostly mild to moderate procedure-associated AEs and less common treatment-related AEs than systemically administered therapies. Additionally, ICV achieves therapeutic goals more consistently than the other intra-CSF delivery methods. To date, there are insufficient data to show dose-related response with intra-CSF delivery. Novel tools are being developed to improve upon intra-CSF delivery that will ideally lead to improved patient outcomes in the near future. Full article

Chemotherapy-induced neutropenia (CIN) and chemotherapy-induced alopecia (CIA) are significant toxicities affecting cancer patients. CIN is a potentially fatal complication of chemotherapy caused by myelosuppression and increased infection susceptibility, while CIA, although not fatal, severely affects treatment adherence and mental health. This study provides a comprehensive comparative analysis of CIN and CIA, focusing on patient, disease, treatment, and genetic risk factors. Key risk factors for CIN and CIA include age, poor performance status, body mass index (BMI), laboratory abnormalities, and pre-existing comorbidities. Both toxicities were significantly associated with breast cancer patients, although CIN patients were more likely to have hematological cancer, and CIA patients were more likely to have solid tumors. Notably, anthracyclines, alkylators, and taxanes frequently induce both toxicities, although their timelines and clinical implications differed. There was no clear overlap between genetic predispositions and toxicities beyond single-nucleotide polymorphisms (SNPs) in the ABCB1 gene. This is the first study to directly compare CIN and CIA, offering insights into personalized oncology care. Understanding the risk factors implicated in the development of CIN and CIA will enable physicians to manage patient outcomes. Full article

This study aims to evaluate the clinical effectiveness of trilaciclib in preventing myelosuppression in patients with esophageal cancer undergoing chemotherapy. Based on the use of trilaciclib, 81 patients were divided into a primary prevention group (PP group, n = 49) and a secondary prevention group (SP group, n = 32). The incidence of myelosuppression, antibiotic usage rate, survival outcomes, and other treatment-related toxicities were analyzed using chi-square tests and Kaplan–Meier survival curves. The incidence of chemotherapy-induced myelosuppression in the SP group was significantly higher than that in the PP group (96.9% vs. 79.6%), with a significantly higher proportion of grade III and above events (37.6% vs. 8.2%, p < 0.05). For chemotherapy-induced neutropenia, the incidence of grade III/IV events in the SP group was significantly higher than in the PP group (28.1% vs. 8.2%, p = 0.017). Additionally, the SP group experienced higher rates and severity of chemotherapy-induced anemia and thrombocytopenia. The PP group provided better protection against grade III/IV leukopenia and neutropenia (p < 0.05). Non-hematological toxicities and efficacy outcomes were similar between groups (p > 0.05). The study is the first to demonstrate that trilaciclib is a safe and effective option for the prevention of myelosuppression in esophageal cancer patients. Full article

Background: Regorafenib (R) and Trifluridine/Tipiracil ± bevacizumab (T) are approved for treating refractory metastatic colorectal cancer (mCRC) but their optimal sequence is unclear. This study describes the characteristics/clinical outcomes of patients with mCRC in U.S. clinical practice treated sequentially with R-T or T-R. Methods: A retrospective cohort study of 818 patients treated with R-T or T-R between January 2015 and November 2022 was conducted using an electronic health record-derived database. The primary objective was to describe the demographic/clinical characteristics and biomarker status of patients treated with R-T or T-R, stratified by treatment line/age. Secondary objectives were to evaluate/estimate the frequency of neutropenia and myelosuppression-related treatments, the number/type of subsequent therapies, time to treatment discontinuation (TTD), and overall survival (OS). Results: Baseline characteristics were similar among patients who received R-T (n = 393) or T-R (n = 425). Lower rates of moderate/severe neutropenia (26%/12% vs. 32%/16%) and granulocyte colony-stimulating factor/erythropoietin use (22% vs. 24%) were observed with R-T versus T-R. The median TTD was 8.7 months and 8.5 months with R-T versus 8.1 months and 7.9 months with T-R as third- and fourth-line treatment, respectively. The median OS was 13.1 months and 11.6 months with R-T versus 11.5 months and 10.3 months with T-R as third- and fourth-line treatment, respectively. Conclusions: This study did not show a statistically significant difference in OS with R-T versus T-R. Although limited by its retrospective nature, the study suggested R-T may be preferable to T-R given the observed reduction in neutropenia/myelosuppression-related treatments. Full article

Background: As COVID-19 has become an epidemic, we conducted an open-label study aimed to identify immunogenicity and reactogenicity of boosters of the BNT162b2 vaccine in a real-world cohort of long-survivor metastatic lung cancer patients (LS-mLC pts). Methods and Analysis: According to the timing of the booster dose (BD) and SARS-CoV-2 infection (Cov-I) during anticancer treatment (ACT), between October 2021 and February 2022, we prospectively enrolled 166 cancer patients into five parallel cohorts. The primary endpoints were seroprevalence of IgG Anti-spike-RBD (anti-S IgG) at two pre-defined timepoints (T1: +30–90 days after BD; T2: +6 months +/− 4 weeks after BD). As an exploratory endpoint, we compared the median pre-vaccination value of four cytokines (IL-6, IL-2R, TNF-α, IL-10) with post-BD values in immunotherapy-treated pts (IO-pts). Results: The anti-S IgG seropositivity rate was 100% at T1 and 98.8% at T2. After 6 months, hybrid immunisation was associated with a higher median anti-S IgG titre compared to vaccine-alone-induced seroconversion (p < 0.0001). In uninfected pts, the median anti-S IgG titre was significantly lower in IO-pts compared to non-IO-pts (p = 0.02); no difference was found when comparing myelosuppressive or not ACT. Among the 68 IO-pts, 5 pts (7.3%) showed a significant increase (≥1.5 fold) of at least two cytokines in post-BD samples, without reporting ir-AEs. Conclusions: Boosters of the COVID-19 mRNA vaccine were effective and safe. In IO-pts without recent Cov-I, additional BDs should be considered to prolong serological immunity. Full article

Functional iron-deficiency anemia (FIDA) is a side effect of many cancer treatments, occurring when chemotherapy drugs damage bone marrow cells, which are responsible for producing red blood cells, due to the myelosuppressive effects of chemotherapy, or to the cancer itself. This study was performed to compare the effects of darbepoetin alfa alone, or in combination with ferric derisomaltose in cancer patients with FIDA, and to elucidate the mechanism underlying the effects in F36E cells. F36E cells treated with darbepoetin alfa showed increased cell viability. AML and GC cells treated with darbepoetin alfa, ferric derisomaltose, or ferric derisomaltose plus darbepoetin alfa showed no induction of apoptosis. The effects of these drugs on the anticancer efficacy of PTX chemotherapy were examined by analyzing cell viability and induction of apoptosis. Darbepoetin alfa, ferric derisomaltose, and ferric derisomaltose plus darbepoetin alfa showed no significant inhibitory effects on the apoptosis-inducing activity of PTX in GC cell lines. Patients with chemotherapy-induced FIDA in Group I receiving ferric derisomaltose plus darbepoetin alfa showed higher hemoglobin levels, transferrin saturation, and ferritin levels compared to those in Group II, treated with darbepoetin alfa alone. In cancer patients with FIDA, the prognosis of anemia treatment was better in the ferric derisomaltose plus darbepoetin alfa combination group than in the group receiving darbepoetin alfa monotherapy. Full article

Background: Colorectal cancer (CRC) is one of the common malignant tumors. Chemotherapeutic agents represented by doxorubicin (DOX) are common adjuvant therapies for patients with advanced CRC. However, DOX suffers from dose-dependent cardiotoxicity and myelosuppression due to a lack of targeting and specificity, which severely limits its clinical application. Methods: Herein, we constructed a zeolitic imidazolate framework-8 (ZIF-8) modified by a novel peptide (LT peptide) to deliver the chemotherapeutic drug doxorubicin (DOX) for the targeted treatment of CRC. Results: In this study, LT-PEG@DOX@ZIF-8 nanoparticles were prepared by a simple method with suitable particle size and zeta potential, which were also capable of pH-responsive drug release. In vitro assays exhibited that LT-PEG@DOX@ZIF-8 nanoparticles were effectively taken up by C26 cells, significantly inhibited cell proliferation, and induced apoptosis. Furthermore, in mice models with colorectal tumors, LT-PEG@DOX@ZIF-8 nanoparticles also displayed specific tumor aggregation and exerted anti-tumor effects to prolong the survival of the mice. Conclusions: In conclusion, LT-PEG@DOX@ZIF-8 provides a promising strategy for the delivery of DOX to effectively treat CRC. Full article

Palbociclib, a dual CDK4/6 kinase inhibitor used for breast cancer, has been explored as a treatment option for rheumatoid arthritis (RA). Preclinical studies have reported palbociclib-induced myelosuppression, but no such effects have been observed in Cdk4 or Cdk6 single-deficient mice. Synoviocyte proliferation-associated in collagen-induced arthritis 1/serum amyloid A-like 1 (SPACIA1/SAAL1) is involved in G1 phase progression. Given that SPACIA1/SAAL1 upregulates CDK6 (but not CDK4) expression, we aimed to determine whether suppressing CDK6 expression alone could prevent synovial hyperplasia without myelosuppression. The effects of CDK6 expression on TNF-α-induced rheumatoid arthritis synovial fibroblast (RASF) proliferation and synovial hyperplasia in collagen-induced arthritis (CIA) mice were investigated by modulating the transcriptional level with a CDK6 expression inhibitor (indole-3-carbinol), CDK6 small interfering RNA (siRNA), and Cdk6-deficient mice. Indole-3-carbinol or CDK6 siRNA inhibited TNF-α-induced RASF proliferation without suppressing CDK4 expression and reduced retinoblastoma protein phosphorylation. In CIA mice, indole-3-carbinol did not cause myelosuppression, considerably delayed CIA onset and progression, and reduced arthritis severity. Cdk6-deficient mice showed similar improvements in CIA pathogenesis but had lower serum anti-type II collagen IgG levels. Notably, synovial hyperplasia was not observed in Cdk6-deficient mice. CIA-synovial hyperplasia depends on CDK6, but not CDK4, expression. Full article

Background: Anemia is a common and progressive clinical manifestation of myelofibrosis that may occur as part of the disease pathogenesis as well as due to the myelosuppressive effects of some treatments, with a substantial impact on quality of life, prognosis, and healthcare resource utilization. Despite these burdens, anemia management has traditionally been a secondary priority to spleen and symptom control, due in part to the limitations of available therapeutic approaches. With the initial regulatory approvals of momelotinib, a Janus kinase 1 (JAK1), JAK2, and activin A receptor type 1 inhibitor that provides anemia-related benefits in addition to addressing splenomegaly and symptoms, re-evaluation of anemia as an early and prominent treatment consideration is warranted. Methods: In this review, we discuss the journey of patients with myelofibrosis and anemia across various severities and clinical scenarios. Results: Summarized are traditional approaches to anemia management and the clinical trial efficacy and safety data that support momelotinib as an option in each setting from mild to severe anemia, including in the context of co-occurring thrombocytopenia. Conclusions: With the availability of momelotinib and other emerging therapies directed at anemia control, early treatment of anemia to avoid progression and support improvement in eligible patients with myelofibrosis should be a primary consideration. Full article