Efficacy and safety of oral versus intravenous cyclophosphamide in treatment of connective tissue disease-related interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) resulting from connective tissue disease (CTD) greatly undermines people's health. Cyclophosphamide (CYC) is a widely used agent in treating CTD-ILD. We compared the efficacy and safety of oral and intravenous CYC in CTD-ILD treatment. METHODS: The retrospectively enrolled CTD-ILD patients were divided into the oral and intravenous CYC groups. The chest high-resolution computed tomography examination, forced vital capacity (FVC), lung carbon monoxide diffusion capacity (Dlco) determinations, and 6 min walk test (6MWT) were performed pre-treatment and at the 3rd, 6th, and 12th months posttreatment. Radiographic ILD severity was assessed using the Warrick score. Krebs Von den Lungen-6, surfactant protein A (SP-A), SP-D, and erythrocyte sedimentation rate (ESR) before and at the 12th month post-treatment were determined. CYC cumulative dose and occurrence of adverse reactions during treatment were recorded. RESULTS: CYC cumulative dose in the intravenous CYC group was reduced. Compared with oral CYC treatment, intravenous CYC caused decreased Warrick score and increased FVC and 6MWT at the 6th month, and elevated DLco at the 3rd and 6th months posttreatment. SP-A, SP-D and ESR levels in both groups were reduced 12 months posttreatment, with a more evident decrease in the intravenous CYC group. Intravenous CYC had lower total adverse reaction incidence. CONCLUSION: Compared with oral CYC, intravenous CYC decreases Warrick score and increases FVC and 6MWT at 6 months posttreatment, and reduces SP-A, SP-D, and ESR levels after 12 months of treatment, which shows low CYC cumulative dose and adverse reaction incidence in treating CTD-ILD.

Observational study of immunosuppressive treatment patterns and outcomes in primary membranous nephropathy: a multicenter retrospective analysis.

BACKGROUND: We evaluated the efficacy of different immunosuppressive regimens in patients with primary membranous nephropathy in a large national cohort. METHODS: In this registry study, 558 patients from 47 centers who were treated with at least one immunosuppressive agent and had adequate follow-up data were included. Primary outcome was defined as complete (CR) or partial remission (PR). Secondary composite outcome was at least a 50% reduction in estimated glomerular filtration (eGFR), initiation of kidney replacement therapies, development of stage 5 chronic kidney disease, or death. RESULTS: Median age at diagnosis was 48 (IQR: 37-57) years, and 358 (64.2%) were male. Patients were followed for a median of 24 (IQR: 12-60) months. Calcineurin inhibitors (CNIs) with or without glucocorticoids were the most commonly used regimen (43.4%), followed by glucocorticoids and cyclophosphamide (GC-CYC) (39.6%), glucocorticoid monotherapy (25.8%), and rituximab (RTX) (9.1%). Overall remission rate was 66.1% (CR 26.7%, PR 39.4%), and 59 (10.6%) patients reached secondary composite outcome. Multivariate logistic regression showed that baseline eGFR (OR 1.011, 95% CI: 1.003-1.019, p = 0.007), serum albumin (OR 1.682, 95% CI: 1.269-2.231, p < 0.001), and use of RTX (OR 0.296, 95% CI: 0.157-0.557, p < 0.001) were associated with remission rates; whereas only lower baseline hemoglobin was significantly associated with secondary composite outcome (OR: 0.843, 95% CI: 0.715-0.993, p = 0.041). CYC use was significantly associated with higher remission (OR 1.534, 95% CI: 1.027-2.290, p = 0.036). CONCLUSIONS: Higher baseline eGFR and serum albumin levels correlated with increased remission rates. Remission rates were lower in patients treated with RTX, while those on GC-CYC showed higher rates of remission. Due to the study's retrospective nature and multiple treatments used, caution is warranted in interpreting these findings.

A multicenter retrospective study on comparing the efficacy and safety of the therapy of intermittent cyclophosphamide and corticosteroids versus rituximab for primary membranous nephropathy.

BACKGROUND: Few clinical studies compare the long-term remission, relapse, and safety of rituximab (RTX) or a combination of intermittent intravenous infusion of cyclophosphamide (CTX) and oral corticosteroid for primary membranous nephropathy (PMN) patients. METHODS: We collected multicenter retrospective data on PMN patients with nephrotic syndrome who received RTX or intermittent intravenous CTX with oral corticosteroids between 1 January 2019 and 31 January 2024. Patients were followed up until two years after receiving immunotherapy. The primary outcomes were a composite of complete or partial remission rates at 6, 12, and 24 months. The secondary outcomes were the relapse and safety evaluation. RESULTS: Forty patients treated with RTX and 27 with the CTX regime were available for analysis. No significant difference in the remission rate at 6, 12, or 24 months was observed between the two groups (p > .05). Kaplan-Meier's survival analysis showed that the relapse-free cumulative survival rate of the RTX group was superior to that of the CTX group (p = .023). Compared with baseline, both the media of urine protein and serum albumin levels in the two groups showed a significant improvement at 6 months and maintained through to the second year. No significant difference in the occurrence of total side effects between the two groups (p = .160). CONCLUSIONS: There was no difference in remission rates and safety between RTX versus intermittent intravenous CTX combined with oral corticosteroid treatment for patients with PMN within 2 years. RTX appeared to have benefits in terms of prolonging relapse-free survival.

The immunostimulatory effects of fucoidan on the cellular and humoral immune response in Wistar rats.

Background: Natural product active ingredients are currently being studied rigorously worldwide and offer a viable substitute for traditional immunotherapy for various medical disorders. Aim: The objective of the study was to investigate the immunostimulatory properties of fucoidan in albino Wistar rats. Methods: For the current study, forty rats were divided into five groups of rats that were used in good condition. In-vivo experiments of fucoidan were carried out in Wistar albino rats, such as the cyclophosphamide-caused myelosuppression, the delayed-type hypersensitivity (DTH) response, the phagocytic activity, the haemagglutinating antibody (HA) titer, and the neutrophil adhesion test. Results: The phagocytic index increased significantly in response to Fucoidan in a dose-dependent manner, as well as enhanced DTH reaction, and HA titer caused by sheep red blood cells sheep red blood cells. Additionally, fucoidan decreased myelosuppression in rats after cyclophosphamide treatment and enhanced neutrophil adhesion with nylon fiber. Conclusion: These findings imply that fucoidan has immunostimulant properties and could potentially utilised to treat immune-depression diseases.

Impact of cyclophosphamide on the morphological and histological changes in polyglycolic acid spacers.

In radiotherapy for pediatric abdominal tumors, determining the effect of concurrent chemotherapy on polyglycolic acid (PGA) spacers is crucial; yet this effect has not been validated. Therefore, we aimed to evaluate the impact of cyclophosphamide (CPA) chemotherapy on the PGA spacer using a rat model. Twenty-four rats were implanted with the spacer, and morphological changes in the spacer were assessed on CT for both the CPA-dosed group (40 mg/kg) and the control group. The size and volume of the spacer were quantified using CT, while the degree of adhesion and microscopic examination of the tissue were determined using pathology specimens. Morphologically, the size of the spacer decreased over time in both the CPA-dosed and control groups, with no significant differences observed between groups. No significant differences in adhesion were observed between the two groups. Macrophages were observed around the PGA fibers, suggesting their involvement in the degradation of the PGA spacer. These results suggest that CPA does not cause significant clinically problematic degradation or adverse tissue reactions to the PGA spacer. This study reinforced the benefits of PGA spacers; however, future research focusing on in vivo longitudinal monitoring of individual rats, as well as on humans, is required.

Anti-obesity and immunomodulatory effects of Allium hookeri leaves cultivated with artificial light of different intensities on immune-depressed obese mice.

This study was conducted to evaluate the effects of Allium hookeri (AH) leaves cultivated with different light-emitting diode (LED) intensities (L: low, 100 µmol/m2/s; M: medium, 150 µmol/m2/s; H: high, 200 µmol/m2/s). Alliin concentration increased as light intensity increased in AH and showed the highest level at LED-H condition. The anti-obesity and immunomodulatory properties of AH were evaluated in a cyclophosphamide (CPA)-induced immunosuppressed obese animal model. C57BL/6 J mice were randomly divided into control (CON), high-fat diet (HFD) control (CON-H), negative control (NC), positive control (PC, ß-glucan, 50 mg/kg body weight (BW)), AH L, M, and H groups. The three kinds of AH extracts were orally administered to the mice at 300 mg/kg BW for 2 weeks. Except for CON and CON-H, all the other groups were intraperitoneally treated with CPA. Epididymal and abdominal fat weight decreased as LED intensity increased while spleen weight increased in the AH groups. Serum glucose decreased as LED intensity increased in the AH groups and H group showed the lowest level. Triglycerides, total, and LDL-cholesterol levels decreased while HDL-cholesterol level increased in the AH groups compared to the NC group. Moreover, AH effectively reduced serum ALT and AST levels and increased the total white blood cell count, particularly elevating lymphocyte and monocyte levels. Furthermore, NK cell activity was higher in the AH groups. These findings suggest that AH cultivated at optimal LED intensity could be used as a novel biomedicine and in pharmacotherapy to treat related diseases to improve public health without any toxicity.

Zein and gum arabic nanoparticles: potential enhancers of immunomodulatory functional activity of selenium-containing peptides.

Food-derived nanomaterials optimizing bioactive peptides is an emerging route in the functional food field. Zein and gum arabic (GA) possess favorable encapsulation properties for controlled release, targeted delivery and stabilization of food bioactive ingredients, and thus are considered as promising carriers for delivery systems. In order to improve the bioavailability of rice selenium-containing peptide TSeMMM (T), the nanoparticles (ZTGNs) containing peptide T, zein and GA have been previously prepared. This study focused on evaluating the immunomodulatory capacity of ZTGNs. The results showed that ZTGNs significantly alleviated cyclophosphamide-induced reduction in immune organ indices and liver glutathione content of mice. There was a significant upregulation observed in the levels of immune-related cytokines IL-6, TNF-α, and IFN-γ as well as their mRNA expression. Moreover, ZTGNs enriched the diversity of the intestinal flora and promoted the proportion of beneficial bacteria. In conclusion, ZTGNs have potential as immunomodulatory enhancers for food bioactive ingredients, providing prospects for further optimization of dietary supplements.

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.

Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.

TBI/Cy followed by auto-HSCT is a good choice next to allo-HSCT for patients with T-LBL/ALL.

The aim of this retrospective study was to evaluate the efficiency and safety of total body irradiation plus cyclophosphamide (TBI/Cy) followed by autogenetic hematopoietic stem cell transplantation (auto-HSCT) in T-LBL/ALL patients that cannot receive allogeneic hematopoietic stem cell transplant (allo-HSCT). Between 2013 and 2023, 24 patients received auto-HSCT following by TBI/Cy, 26 patients underwent allo-HSCT, all patients achieved completed hematopoietic reconstitution after HSCT. The progression free survival (PFS) and overall survival (OS) had no statistically significant differences between the two groups (P = 0.791, HR 1.127, 95%CI 0.456-2.785; P = 0.456, HR 0.685, 95%CI 0.256-1.828). Although the cumulative incidence of relapse was lower for patients who received allo-HSCT than auto-HSCT (P = 0.033, HR 3.707, 95%CI 1.188-11.570, 2-year relapse 11.5% vs. 33.3%), the incidence of non-relapse mortality (NRM) was higher than that in the auto-HSCT group (P = 0.014, HR 0.000, 95%CI -1.000 - -1.000, 2-year NRM, 23.1% vs. 0%). Trough Landmark analysis, the two groups showed a statistically significant difference in 3-year PFS and 4-year OS curves (Figure S2A&B, P = 0.039, HR 0.426, 95%CI 0.163-1.117; P = 0.014, HR 0.317, 95%CI 0.113-0.887). By COX analysis, poor baseline performance status (ECOG-PS ≥ 2) and CNS involvement were risk factors for PFS and OS. In conclusion, TBI/Cy followed by auto-HSCT is a good choice next to allo-HSCT for patients with T-LBL/ALL.