Search Results (106)

Background: Wugeng San (WGS) is a traditional Tibetan medicinal preparation that has long been used to treat inflammatory and arthritic conditions. However, its contemporary pharmacological validation and the mechanisms underlying its action in rheumatoid arthritis (RA) have not been fully investigated. Objective: For the first time, this study aimed to systematically investigate the therapeutic effects of WGS on RA, identify its potential targets, and elucidate its action mechanisms. Methods: This study, as the first comprehensive investigation of WGS in RA, employed integrated multiple approaches including chemical component identification via UPLC-Q-TOF/MS, network pharmacology, bioinformatics, machine learning, and in vivo efficacy assessment and mechanism verification in a collagen-induced arthritis (CIA) rat model, a widely accepted experimental model that mimics the key pathological features of RA. Results: The results demonstrated that WGS reduced the severity of arthritis in a dose-dependent manner, as evidenced by decreased paw swelling, normalized body weight, and restored levels of pro- and anti-inflammatory cytokines. The high dose of WGS (252 mg/kg) showed an effect comparable to that of methotrexate (0.2 mg/kg). Histological analysis revealed that WGS reduced synovial hyperplasia, cartilage erosion and bone destruction, decreased osteoclast numbers, and promoted osteoblast activity. Eighty-four compounds were identified using UPLC-Q-TOF/MS. Network pharmacology and machine learning analyses indicated SYK as a key target enriched in the NF-κB signaling and osteoclast differentiation pathways. Experimental validation confirmed that WGS suppressed the phosphorylation of SYK and NF-κB pathway components (p65, IκBα, and IKKα/β), decreased MMP1/MMP3 levels, and modulated the Bax/Bcl-2 ratio to promote apoptosis. Conclusions: In conclusion, WGS exhibits strong anti-arthritic effects through “multi-component, multi-target, and multi-pathway” mechanisms, likely attributable to the inhibition of the SYK/NF-κB signaling axis, suppression of matrix degradation, and regulation of cellular apoptosis. This research offers a pharmacological basis for repurposing WGS as a promising natural candidate for RA therapy. Full article

Epstein–Barr virus (EBV)-positive primary central nervous system lymphoma (PCNSL) is a rare entity typically associated with profound immunosuppression, most commonly in transplant recipients or individuals with HIV. We report a case of EBV-positive PCNSL arising in a 75-year-old male with myasthenia gravis receiving chronic mycophenolate mofetil (MMF) therapy outside the transplant setting. The patient presented with progressive neurological deficits, and brain magnetic resonance imaging demonstrated multiple enhancing lesions. Stereotactic biopsy revealed diffuse large B-cell lymphoma of non–germinal center subtype with immunoblastic features and EBV-encoded RNA (EBER) positivity, confirming EBV-positive PCNSL. MMF was discontinued, and the patient was treated with rituximab and high-dose methotrexate, resulting in stable disease. This case highlights that prolonged MMF therapy may confer sufficient immunosuppression to permit EBV-driven lymphoproliferative disease even in non-transplant patients. Early recognition, withdrawal of immunosuppression, and initiation of methotrexate-based chemotherapy can lead to favorable outcomes. Full article

Background and Clinical Significance: Neurosarcoidosis (NS) is a rare manifestation of systemic sarcoidosis involving the central nervous system, with highly variable neurological and endocrine presentations. Among these, anterior pituitary dysfunction is particularly uncommon and diagnostically challenging. Case Presentation: We report the case of a 37-year-old woman with a 4-year history of secondary amenorrhoea and an initially suspected pituitary microadenoma, who was ultimately diagnosed with probable NS presenting with multiaxial anterior pituitary insufficiency. Early magnetic resonance imaging (MRI) revealed a small pituitary lesion and isolated pituitary stalk thickening, without other central nervous system abnormalities. Subsequent imaging demonstrated contrast-enhancing lesions involving the meninges and cranial nerves, along with progression of pituitary stalk involvement and loss of the posterior pituitary bright spot. Further evaluation confirmed systemic sarcoidosis. High-dose corticosteroid therapy led to partial clinical and radiological improvement; however, relapse necessitated methotrexate, and persistent pituitary hormone deficiencies required long-term hormonal replacement. Conclusions: This case highlights the diagnostic complexity of NS presenting with isolated endocrine dysfunction and subtle imaging findings. It underscores the need to consider systemic sarcoidosis in patients with unexplained hypopituitarism. Full article

Neurological complications, particularly seizures, represent a significant and often under-recognized clinical challenge in pediatric hematologic malignancies. Distinguishing CNS leukemia-associated epilepsy from chemotherapy-induced neurotoxicity is critical for optimizing therapy but remains difficult due to overlapping clinical presentations. This review highlights the distinct molecular mechanisms underlying these two entities. CNS leukemia-associated seizures are primarily driven by blood–brain barrier (BBB) disruption following leukemic infiltration, which triggers a neuroinflammatory cascade involving pro-inflammatory cytokines such as IL-6 and TNF-α, and impairs glutamate homeostasis. In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility—including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes—as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population. Full article

Primary central nervous system lymphoma (PCNSL) is an aggressive malignancy for which early management decisions frequently occur within neurosurgical workflows prior to oncologic treatment. In this retrospective single-center study, we aimed to explore whether early neurosurgical workflow characteristics are associated with survival outcomes in patients with PCNSL. Consecutive adult patients diagnosed with PCNSL between 2012 and 2022 were included, and the variables of interest comprised pre-biopsy corticosteroid exposure, the interval between diagnostic magnetic resonance imaging (MRI) and stereotactic biopsy, and the time from biopsy to initiation of high-dose methotrexate–based induction therapy. All patients were treated under a standardized hematology protocol to limit systemic treatment heterogeneity. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of diagnostic biopsy, and survival analyses were performed using Kaplan–Meier methods and log-rank testing. Twenty-nine patients met the inclusion criteria. Median OS and PFS were not reached in steroid-naïve patients, whereas pre-biopsy corticosteroid exposure was associated with consistently shorter survival trajectories, with a clear separation of the survival curves, despite conventional statistical significance not being reached. Similarly, median OS and PFS were not reached in patients undergoing biopsy within 7 days of MRI, and an MRI-to-biopsy interval exceeding 7 days demonstrated an unfavorable survival trajectory compared with earlier biopsy; biopsy-to-induction timing did not show a measurable association with early survival outcomes. Established prognostic stratification using Memorial Sloan–Kettering Cancer Center classes showed expected survival discrimination within the cohort, supporting internal validity. Given the limited sample size and retrospective design, all findings should be interpreted as exploratory associations rather than evidence of causality. These results suggest that early neurosurgical workflow characteristics, particularly empiric pre-biopsy corticosteroids avoidance and diagnostic delay minimization, may be associated with early survival trajectories in PCNSL and warrant further evaluation in larger prospective studies. Full article

Psoriasis is a chronic inflammatory disease that affects up to 3% of the global population. In recent years, monoclonal antibodies targeting key cytokines underlying skin lesions and joint involvement in the course of psoriasis, i.e., TNF-α, IL-17, and IL-23, have been increasingly used due to their high effectiveness and favorable safety profile. Numerous studies have been conducted analyzing the influence of cytokine inhibitors on non-specific inflammatory markers. However, only a limited number of studies on the effect of methotrexate (MTX) therapy on blood-count-derived inflammatory indices in patients with plaque psoriasis have been published so far. The study aims to analyze and compare the impact of methotrexate and biological drugs on the dynamics of selected blood-count-derived inflammatory indices in psoriatic patients. The analysis involved 182 patients receiving biological therapy, which resulted in a total of 219 treatment cycles (TCs) and 48 patients treated with therapeutic doses of MTX (48 TCs). In the biological subgroup, there were six TCs with an inhibitor of IL-12/23, 58 TCs with IL-17A inhibitors, 22 TCs with an inhibitor of IL-17AF, 113 TCs with IL-23 inhibitors, and 20 TCs with TNF-alfa inhibitors. A comparison between patients receiving biological treatment regardless of the drug and patients receiving MTX was conducted. Themajor factors determining the duration of MTX therapy were older age at the time of therapy initiation, a later onset of psoriasis, and a higher burden of comorbidities. Furthermore, the strongest impact on the average inflammatory state over time in patients treated with methotrexate was associated with comorbidities, male gender, and older age. Contrary to MTX therapy, patients receiving biological drugs were characterized by lower values of most assessed blood-count-derived inflammatory biomarkers at week 40 compared to baseline. It was confirmed that biologics and MTX treatment modify the dynamics of blood-count-derived inflammatory biomarkers in a different manner. Full article

Background/Objectives: Methotrexate (MTX) is a cornerstone drug used to treat immune-mediated inflammatory diseases (IMIDs) in low doses (10–30 mg/week), and malignancies in high doses (5000 mg/m²/2 weeks). Its active metabolites, Methotrexate polyglutamates (MTX-PG_2–5), quantified in erythrocytes, are associated with efficacy. This study aimed to compare erythrocyte MTX-PG concentrations in patients with IMIDs and pediatric acute lymphoblastic leukemia (ped-ALL) treated with low-dose or high-dose MTX, respectively, and to identify clinical, demographic, and treatment-related factors influencing their concentration. Methods: A total of 567 patients with rheumatoid arthritis, juvenile idiopathic arthritis, Crohn’s disease, sarcoidosis, and ped-ALL were included. Erythrocyte MTX-PG concentration data was collected after 3 months (2.5 months for ped-ALL patients) of MTX-use. Multivariate linear regressing modelling adjusting for age, sex, body mass index (BMI), smoking status, starting MTX dose, route of MTX administration, use of predniso(lo)ne, disease-modifying anti-rheumatic drugs (DMARDs), and folic (or folinic) acid was performed. Results: Intravenous high-dose MTX increased MTX-PG_4&5 accumulation. Despite 50-fold higher doses in ped-ALL, MTX-PG_2–5sum concentrations were similar to those seen with subcutaneous low-dose MTX used in IMIDs. Age positively influenced MTX-PG concentrations, while DMARD use reduced MTX-PG_2–3&5 concentrations. Interestingly, predniso(lo)ne use was associated with higher MTX-PG_4&5 concentrations and folic (or folinic) acid with higher MTX-PG_3–5 concentrations. Conclusions: This is the first study to compare erythrocyte MTX-PG concentration in low-dose and high-dose patients. Intravenous high-dose MTX administration increased long-chain MTX-PG_4&5 concentrations, with MTX-PG_2–5sum concentrations similar compared to low-dose subcutaneous MTX use. This study demonstrated that route of administration, age, and concomitant therapies such as DMARDs, predniso(lo)ne, and folic (or folinic) acid significantly influence MTX-PG concentrations. Full article

Background: Tumor necrosis factor-α (TNFα) inhibitors have significantly improved outcomes in children with non-systemic juvenile idiopathic arthritis (JIA), achieving long-term clinical remission for many patients. However, the optimal strategy for TNF-α inhibitor withdrawal remains unknown, whether through abrupt discontinuation, gradual dose reduction, or interval extension. Objective: We aim to identify patient-, disease-, and treatment-related predictors of successful TNF-α inhibitor withdrawal in children with non-systemic JIA. Methods: In this prospective, randomized, open-label, single-center study, 76 children with non-systemic JIA in stable remission for ≥24 months on etanercept or adalimumab were enrolled. At the time of TNF-α inhibitor discontinuation, all patients underwent a comprehensive evaluation, including a clinical examination, laboratory tests (serum calprotectin [S100 proteins] and high-sensitivity C-reactive protein [hsCRP]), and advanced joint imaging (musculoskeletal ultrasound and magnetic resonance imaging [MRI]) to assess subclinical disease activity. Patients were randomized (1:1:1, sealed-envelope allocation) to one of three predefined tapering strategies: (I) abrupt discontinuation; (II) extension of dosing intervals (etanercept 0.8 mg/kg every 2 weeks; adalimumab 24 mg/m² every 4 weeks); or (III) gradual dose reduction (etanercept 0.4 mg/kg weekly; adalimumab 12 mg/m² every 2 weeks). Follow-up visits were scheduled at 3, 6, 9, 12, and 18 months to monitor for disease relapse. Results: Higher baseline Childhood Health Assessment Questionnaire (CHAQ) scores (≥2), elevated serum calprotectin [S100 proteins] and hsCRP levels at withdrawal, imaging evidence of subclinical synovitis, and a history of uveitis were all significantly associated with increased risk of flare. No significant associations were found for other clinical or demographic characteristics. Conclusions: Early significant clinical response, absence of subclinical disease activity, and concomitant low-dose methotrexate therapy were key predictors of sustained drug-free remission. These findings may inform personalized strategies for biologic tapering in pediatric JIA. Full article

Objectives: To determine the incidence of delayed methotrexate elimination (DME) and acute kidney injury (AKI) and their associations with clinical outcomes in patients receiving high-dose methotrexate (HDMTX) for cancer treatment. Methods: The HDMTX European Registry collected medical records data from 12 institutions in 5 European countries to investigate the clinical practice patterns of healthcare providers utilizing HDMTX for cancer treatment. Cancer types included were acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), non-Hodgkin lymphoma (NHL), osteosarcoma, and other CNS cancers. Primary endpoints were the incidence of DME and AKI; secondary endpoints were clinical outcomes, including hospital length of stay (LOS), delay in the subsequent course of treatment, methotrexate dose reduction, and omission of next course of treatment. Associations between the primary and secondary endpoints were analyzed with Chi-square and Wilcoxon rank-sum tests. Results: Among the 2501 total HDMTX courses analyzed, DME occurred in 302 courses (12.1%), and AKI in 384 courses (15.4%). DME incidence was highest in courses for PCNSL (18.2%) and NHL (17.2%); AKI incidence was highest in ALL courses (21.0%). Incidence of DME and AKI varied by age and methotrexate infusion duration among the different cancer types. Occurrence of DME was associated with longer delays prior to the next course of treatment, longer hospital LOS, and more frequent methotrexate dose reductions and dose omissions. Conclusions: While HDMTX is a very effective and safe treatment, administration of efficacious doses of methotrexate can lead to AKI and DME, and no single or combination of patient or treatment factors was found to reliably predict their occurrence. Thus, diligent monitoring of methotrexate levels is imperative for early detection and prompt management of nephrotoxicity in all settings where HDMTX treatment is administered. Full article

Background: Primary central nervous lymphoma (PCNSL) is a rare, aggressive, non-Hodgkin’s lymphoma. Outcomes are poor with standard induction of high-dose methotrexate (HD-MTX)-based regimens and consolidation. We present retrospective data from the Georgia Cancer Center. Methods: A single retrospective chart review was conducted on all PCNSL patients from 2013 to 2023 to assess for various factors influencing care. Results: Of a total of 38 PCNSL patients, 6 died and 2 were lost to follow-up prior to therapy initiation, leading to a total of 30 patients for analysis. The median age was 62.3 (21–82 years). One patient had HIV/AIDS. Two patients were on immunosuppression for either kidney transplant or multiple sclerosis (MS). The HIV and MS cases were Epstein-Barr Virus (EBV)-positive. Completion of ≥six cycles of induction was predictive of response. Conclusions: PCNSL remains an area of high unmet need. Recent studies have shown that HD-MTX-based therapy and autologous stem cell transplantation afterwards leads to improved outcomes regardless of age; however, non-relapse mortality is important to consider. Our data from a primarily elderly and sub-rural cohort reiterate the efficacy of combination chemoimmunotherapy and impact of induction cycle number on response, regardless of age. A multidisciplinary approach and targeted agent maintenance should be considered to improve outcomes in the elderly. Full article

Background: CP (CP) and HCP (HCP) are rare and high-risk conditions, often historically managed with radical intervention and associated with hemorrhage and fertility loss. Objective: To summarize current evidence on the conservative, fertility-preserving management of cervical and heterotopic cervical pregnancies and to illustrate a stepwise pharmacologic protocol applied in our tertiary center. Methods: A narrative literature review (PubMed, Scopus, Web of Science; inception—July 2025) was conducted using the following key terms: “CP,” “HCP,” “methotrexate,” “mifepristone,” “misoprostol,” “uterine artery embolization,” “hysteroscopy,” and “Doppler ultrasound.” We integrated a personal institutional case that applied stepwise pharmacologic priming, Doppler-guided surveillance, and delayed evacuation. Results: Evidence—primarily from case reports and small series—supports conservative, multi-modal strategies combining systemic or local methotrexate ± mifepristone, timed to Doppler-confirmed vascular regression, before surgical intervention. Adjuncts such as misoprostol, hysteroscopic resection, balloon tamponade, and uterine artery embolization further reduce hemorrhage risk while maintaining fertility. Our case utilized a novel, incremental dosing strategy of mifepristone followed by methotrexate, a week-long interval to confirm vascular involution via Doppler, and delayed suction curettage with minimal blood loss. Conclusions: Conservative, imaging-guided management is promising for reducing hemorrhagic complications and preserving fertility in CP/HCP. Future multicenter registries and standardized Doppler-based protocols are urgently needed to refine decision-making and optimize outcomes. Full article

Background: High-dose methotrexate (HDMTX) is widely used for acute lymphoblastic leukaemia (ALL), but its pharmacokinetic (PK) variability and toxicity require therapeutic drug monitoring (TDM). Our 10-year retrospective study investigated HDMTX PK parameters and their associations with renal and hepatic biomarkers in an Italian cohort of adult patients with ALL. Methods: Plasma MTX concentrations [MTX C(p)] were measured at 24-, 48-, and 72 h post-infusion. PK modelling was performed to calculate area under the curve (AUC_{0 → 72 h}) and half-life (t½). Creatinine, total bilirubin, and sample quality indices were retrieved from routine clinical laboratory analyses. Results: Mean (±SEM) MTX plasma concentrations were 36.09 ± 15.53 μmol/L, 0.93 ± 0.43 μmol/L, and 0.30 ± 0.07 μmol/L at 24, 48, and 72 h, respectively, with marked inter-patient variability. PK analysis showed a mean AUC_{0 → 72 h} of 112.85 ± 34.09 h·μmol/L and a t½ of 17.15 ± 2.40 h. MTX C(p) and AUC_{0 → 72 h} showed significant positive correlations with serum creatinine at all time points, confirming renal function as a major MTX clearance determinant. Age moderated the relationship at 72 h, with younger patients showing stronger correlations. Hepatic function measured by total bilirubin also correlated with MTX C(p) and AUC_{0 → 72 h} at 48 and 72 h, especially in younger patients, suggesting a hepatic contribution to MTX variability. No associations were found between the PK parameters and lipemic, icterus, or haemolysis indices. Conclusions: These findings highlight the value of integrating renal and hepatic biomarkers into HDMTX drug monitoring protocols. Such biomarker-informed TDM may improve the safety and efficacy by identifying patients at risk of delayed clearance and toxicity, especially younger individuals or those with renal insufficiency. Full article

Bing–Neel syndrome (BNS), a rare complication of Waldenström macroglobulinemia (WM), is caused by the direct infiltration of lymphoplasmacytic cells into the central nervous system (CNS). Since clinical manifestations are heterogeneous and may overlap with IgM-related neuropathies, BNS is often under-recognized and diagnosed late. The incidence of BNS has been reported to be approximately 1% of patients with WM. Because of its extreme rarity, there are no prospective studies on BNS. In 2025, a consensus panel from the 12th international workshop on WM updated the guidelines for BNS, recognizing zanubrutinib as a standard therapy, clarifying imaging and cerebrospinal fluid (CSF) assessments during follow-up, and introducing revised response categories. Although the incidence of BNS is approximately 1% of WM, it decreases overall survival compared to WM alone, and early deaths were reported in historical series. Diagnostic confirmation requires a high index of suspicion and a multimodal approach combining MRI of the brain and spine with gadolinium, CSF cytology and flow cytometry, molecular testing such as MYD88 L265P, and occasionally tissue biopsy. Importantly, MYD88 L265P is also observed in most cases of diffuse large B-cell lymphoma of the CNS and is therefore not disease-specific. Differentiation from IgM-mediated neuropathies is critical because management strategies markedly differ. Historically, high-dose methotrexate- or cytarabine-based chemotherapy, intrathecal therapy, and radiotherapy have been used; however, responses varied, and toxicity was considerable. In contrast, CNS-penetrant Bruton tyrosine kinase (BTK) inhibitors have reshaped therapeutic strategies. Retrospective data support durable responses with ibrutinib, tirabrutinib, and zanubrutinib, while early findings suggest that non-covalent BTK inhibitors expand options for relapsed or refractory cases. Herein, we synthesize current evidence on epidemiology, pathophysiology, and diagnostic work-up. We also outline therapeutic recommendations integrating the genotype, disease pattern, and patient fitness and conclude with unmet needs and future directions. Full article

Background/Objectives: Hematological toxicities (i.e., neutropenia, thrombocytopenia, and anemia), are common chemotherapy complications and may be exacerbated by renal or hepatic impairment due to altered drug exposure. This study assessed the association between renal and hepatic impairment and hematologic toxicities during chemotherapy in routine clinical practice. Methods: A single-center retrospective cohort study using the Utrecht Patient Oriented Database (UPOD) identified all chemotherapy administrations at the University Medical Centre Utrecht between 2011 and 2024. Regimens administered in ≥10 patients and ≥5 renally (GFR < 60 mL/min) or hepatically (bilirubin or AST > 1× ULN) impaired patients were included in descriptive analyses. Cox proportional hazards models estimated associations between organ impairment and grade ≥ 3 hematologic toxicities for regimens with ≥10 events per toxicity endpoint. Results: Overall, 4489 patients were included in renal analyses and 6218 in hepatic analyses, with smaller endpoint-specific subgroups for survival analyses. Renal impairment was associated with grade ≥ 3 neutropenia (HR: 1.43 [95% CI: 1.18–1.73]), thrombocytopenia (HR: 1.46 [95% CI: 1.15–1.86], and anemia (HR: 1.66 [1.27–2.16]). Hepatic impairment was similarly associated with neutropenia (HR: 1.25 [95% CI: 1.11–1.40]), thrombocytopenia (HR: 1.33 [95% CI: 1.13–1.57]), and anemia (HR: 1.62 [95% CI: 1.34–1.95]). Cyclophosphamide (pro-drug) regimens showed higher toxicity risk in renally impaired patients and reduced risk in hepatically impaired patients. Etoposide, melphalan and methotrexate were associated with increased toxicity in hepatically impaired patients. Conclusions: Renal and hepatic impairment significantly increase chemotherapy-induced hematologic toxicity. Several high-risk chemotherapy regimens were identified; however, larger multi-center datasets are needed to refine dosing guidance based on renal and hepatic function. Full article