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International Immunopharmacology Jun 2024IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension....
IIrbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has been widely employed in the medical field for its effectiveness in managing hypertension. However, there have been no documented investigations regarding the immunostimulatory properties of IRB. To address this gap, this study has been performed to assess the neuroprotective impact of IRB as an immunostimulatory agent in mitigating acute neurotoxicity induced by cyclophosphamide (CYP) in rats. mRNA levels of nuclear factor erythroid 2 (Nrf-2), interleukin (IL)-18, IL-1β, and MMP-1 have been assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the levels of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) has been evaluated to assess the oxidative stress. Additionally, macrophage inflammatory protein 2 (MIP2) has been evaluated using enzyme-linked immunosorbent assay (ELISA). Western blotting has been used to investigate the protein expression of nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) and caspase-1 (CASP-1), along with an assessment of histopathological changes. Administration of IRB protected against oxidative stress by augmenting the levels of GSH and SOD as well as reducing MDA level. Also, administration of IRB led to a diminishment in the brain levels of MIP2 and MMP1. Furthermore, it led to a suppression of IL-1β and IL-18 levels, which are correlated with a reduction in the abundance of NLRP3 and subsequently CASP-1. This study provides new insights into the immunomodulatory effects of IRB in the context of CYP-induced acute neurotoxicity. Specifically, IRB exerts its effects by reducing oxidative stress, neuroinflammation, inhibiting chemokine recruitment, and mitigating neuronal degeneration through the modulation of immune markers. Therefore, it can be inferred that the use of IRB as an immunomodulator has the potential to effectively mitigate immune disorders associated with inflammation.
Topics: Animals; Cyclophosphamide; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Irbesartan; Male; Rats; Oxidative Stress; Neurotoxicity Syndromes; Neuroprotective Agents; Signal Transduction; Immunomodulation; Rats, Wistar
PubMed: 38801809
DOI: 10.1016/j.intimp.2024.112336 -
Zhonghua Fu Chan Ke Za Zhi May 2024To investigate the effect of rare ginsenosides (RGS) on reproductive injury induced by cyclophosphamide (CP) in female rats. Twenty-four female rats were divided into...
To investigate the effect of rare ginsenosides (RGS) on reproductive injury induced by cyclophosphamide (CP) in female rats. Twenty-four female rats were divided into four groups [normal control (NC), RGS, CP, and CP+RGS group] with 6 rats in each group. CP group (the model group) and CP+RGS group (the treatment group) were intraperitoneally injected with CP 30 mg/kg for 5 days for modeling, and CP+RGS group was given RGS intragastric intervention. General growth status of rats in each group was observed, the organ index was calculated, and the pathological changes of ovary, uterus, liver and kidney were observed by hematoxylin-eosin staining. Serum levels of estradiol, follicle stimulating hormone (FSH), luteinizing hormone (LH), pro-inflammatory factors interleukin (IL) 6, IL-1β, tumor necrosis factor-α were detected. The urine samples were collected after RGS treatment for metabonomics analysis. Metabolomic profiling based on ultra performance liquid chromatography (UPLC) coupled with mass spectrometry (MS) was used to analyze and determine the urine metabolites of rats in each group. Compared with NC group, the ovary index of CP group [(0.054±0.015) %] was significantly decreased (<0.05), the uterus index [(0.293±0.036) %] and estradiol level [(62.9±6.4) pmol/L] were significantly decreased (all <0.01), serum levels of FSH, LH, IL-6 and IL-1β [(20.4±1.0) U/L, (29.0±3.0) U/L, (185.4±28.6) ng/L, (72.9±2.0) ng/L, respectively] were significantly increased (all <0.01). Compared with CP group, the ovary index in CP+RGS group [(0.075±0.010) %] was significantly increased (<0.05), serum estradiol level [(122.1±16.2) pmol/L] was significantly increased (<0.01), serum FSH, IL-1β and IL-6 levels [(16.7±1.0) U/L, (111.8±17.4) ng/L, (60.1±2.2) ng/L, respectively] were significantly decreased (all <0.01). Metabonomics analysis results showed that, a total of 352 metabolites were detected in urine, of which 12 were found to be potential markers associated with reproductive injury according to the screening standard. After treatment with RGS, differential metabolites were improved in the direction of NC group. Pathway enrichment suggests that the therapeutic effect of RGS was related to multiple metabolic pathways, including purine metabolism and taurine and hypotaurine metabolism. RGS might reduce inflammation and thus ameliorate the damage caused by CP to the reproductive system of female rats by affecting purine metabolism and other pathways.
Topics: Animals; Female; Rats; Cyclophosphamide; Metabolomics; Ginsenosides; Follicle Stimulating Hormone; Estradiol; Ovary; Uterus; Rats, Sprague-Dawley; Luteinizing Hormone; Chromatography, High Pressure Liquid; Interleukin-6; Disease Models, Animal; Interleukin-1beta; Tumor Necrosis Factor-alpha; Liver; Mass Spectrometry; Kidney
PubMed: 38797569
DOI: 10.3760/cma.j.cn112141-20240116-00038 -
European Journal of Radiology Jul 2024To investigate the value of quantitative contrast-enhanced ultrasonography (CEUS) in assessing and predicting early therapy response of non-Hodgkin's lymphoma (NHL).
OBJECTIVE
To investigate the value of quantitative contrast-enhanced ultrasonography (CEUS) in assessing and predicting early therapy response of non-Hodgkin's lymphoma (NHL).
METHODS
Fifty-six cases of NHL were studied using CEUS before and after three cycles of R-CHOP / CHOP. Quantitative parameters such as arrival time (ATM), time to peak (TTP), △T = TTP-ATM, area under the gamma curve (Area), curve gradient (Grad), wash-out time (WT), base intensity (BI), peak intensity (PI) and ΔI = PI-BI were compared between the lymphoma and normal lymph nodes before and at mid-treatment, respectively. Changes in quantitative CEUS parameters were also compared between complete response (CR) and incomplete response(non-CR) groups. Besides, the correlation analysis was performed between pretreatment PI and changes in quantitative parameters.
RESULTS
After three cycles of R-CHOP/CHOP, S/L (P < 0.001), PI (P = 0.002), ΔI (P < 0.001), Grad (P < 0.001), and Area (P < 0.001) of NHL were significantly decreased. The CR group and non-CR group only differed in ATM before treatment. In contrast, there was no statistical difference in any of the parameters between the two groups at mid-treatment. Finally, a significant correlation was observed between pre-treatment PI and PI% (r = 0.736, P < 0.001).
CONCLUSIONS
CEUS is promising for the assessment of response of NHL to R-CHOP/CHOP. Intra-lesion perfusion changes take precedence over morphological changes suggesting treatment efficacy. Pre-treatment ATM values may help to suggest efficacy outcomes and pre-treatment PI values may be a valid predictor of lymphoma perfusion response.
Topics: Humans; Male; Female; Lymphoma, Non-Hodgkin; Middle Aged; Contrast Media; Prospective Studies; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Ultrasonography; Case-Control Studies; Adult; Cyclophosphamide; Aged; Vincristine; Doxorubicin; Prednisone; Rituximab; Image Enhancement; Sulfur Hexafluoride; Reproducibility of Results; Phospholipids; Sensitivity and Specificity; Young Adult
PubMed: 38796885
DOI: 10.1016/j.ejrad.2024.111525 -
The Lancet. Haematology Jun 2024Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study.
BACKGROUND
Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL.
METHODS
Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375).
FINDINGS
86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown).
INTERPRETATION
Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial.
FUNDING
Bristol-Myers Squibb.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Humans; Male; Female; Aged; Middle Aged; Azacitidine; Administration, Oral; Bendamustine Hydrochloride; Gemcitabine; Lymphoma, Follicular; Deoxycytidine; Depsipeptides; Antineoplastic Combined Chemotherapy Protocols; Antimetabolites, Antineoplastic; Aged, 80 and over
PubMed: 38796193
DOI: 10.1016/S2352-3026(24)00102-9 -
Nanotechnology Jun 2024Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH)...
Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and GSH S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally,tumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.
Topics: Chlorambucil; Prodrugs; Glutathione; Humans; Micelles; Animals; Ethacrynic Acid; Nanoparticles; Mice; Glutathione S-Transferase pi; Apoptosis; Cell Line, Tumor; Antineoplastic Agents; Polyethylene Glycols; Glutathione Transferase; Drug Carriers; Drug Liberation
PubMed: 38788695
DOI: 10.1088/1361-6528/ad501a -
Biomolecules May 2024berries contain many compounds with potential benefits for human health. The food flavonoids quercetin and rutin, found in significant amounts in the fruits of , are...
berries contain many compounds with potential benefits for human health. The food flavonoids quercetin and rutin, found in significant amounts in the fruits of , are known to have favourable effects on animal and human organisms. However, data on the effect of flavonols isolated from black chokeberry on immune functions during immunosuppression are not available in the literature. Thus, the aim of this study was to evaluate the effect of flavonol fraction isolated from fruits, in comparison with pure quercetin and rutin substances, on the dysfunctional state of rat thymus and spleen in immunodeficiency. The study was performed on Wistar rats. The animals were orally administered solutions of the investigated substances for 7 days: water, a mixture of quercetin and rutin and flavonol fraction of . For induction of immunosuppression, the animals were injected once intraperitoneally with cyclophosphamide. Substance administration was then continued for another 7 days. The results showed that under the influence of flavonols, there was a decrease in cyclophosphamide-mediated reaction of lipid peroxidation enhancement and stimulation of proliferation of lymphocytes of thymus and spleen in rats. At that, the effect of the flavonol fraction of aronia was more pronounced.
Topics: Animals; Photinia; Cyclophosphamide; Rats; Rats, Wistar; Fruit; Thymus Gland; Flavonols; Spleen; Male; Plant Extracts; Immunosuppression Therapy; Quercetin; Lipid Peroxidation; Immunosuppressive Agents; Cell Proliferation; Rutin
PubMed: 38785985
DOI: 10.3390/biom14050578 -
JPMA. the Journal of the Pakistan... May 2024To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis. (Observational Study)
Observational Study Comparative Study
OBJECTIVES
To compare the efficacy of mycophenolate mofetil with intravenous cyclophosphamideas induction therapy in lupus nephritis.
METHODS
The observational, prospecrive, cohort study was conducted at the Rheumatology Department of Fatima Memorial Hospital, Lahore, Pakistan, from July 2016 to June 2019, and comprised lupus nephritis patients. For induction therapy, the patients were assigned at the discretion of the treating rheumatologist to mycophenolate mofetil group MMF, and intravenous cyclophosphamide group CYC. The latter group was further divided into NIH subgroup that received the therapy as per the protocol of the National Institutes of Health, and ELNT subgroup which recived the therapy as per the Euro Lupus Nephritis Trial protocol. Maintenance therapy in all groups was mycophenolate mofetil. Tacrolimus was added in case of non-response. The outcome was the achievement of complete renal response at 6, 12 and 24 months. Data was analysed using SPSS 26.
RESULTS
Of the 131 patients, 126(96.2%) were females. The overall mean age was 27±7.7 years. There were 58(44.2%) patients in group MMF and 73(55.7%) in group CYC, which had subgroup NIH 46(63%) and subgrpup ELNT 27(37%). The complete renal response rates at 6, 12, and 24 months were 22 (43.1%), 35 (71.4%), and 40(83.3%) for group MMF; 5(12.5%), 9(22%) and 24 (58.5%) for subgroup NIH, and 6(26.1%), 8(36.4%) and 14(63.6%) for subgroup ELNT. Group MMF outcomes were significantly better than the rest (p<0.05).
CONCLUSIONS
Mycophenolate mofetil induction therapy was more effective than intraveenous cyclophosphamide in terms of achieving remission at 6, 12 and 24 months.
Topics: Humans; Lupus Nephritis; Mycophenolic Acid; Cyclophosphamide; Female; Adult; Pakistan; Male; Immunosuppressive Agents; Tertiary Care Centers; Young Adult; Treatment Outcome; Cohort Studies; Tacrolimus; Induction Chemotherapy; Remission Induction
PubMed: 38783432
DOI: 10.47391/JPMA.8694 -
American Journal of Hematology Jul 2024In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether... (Comparative Study)
Comparative Study
Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow...
In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.
Topics: Humans; Middle Aged; Leukemia, Myeloid, Acute; Male; Female; Aged; Transplantation Conditioning; Bone Marrow Transplantation; Graft vs Host Disease; Peripheral Blood Stem Cell Transplantation; Remission Induction; Transplantation, Haploidentical; Cyclophosphamide; Europe; Registries; Pathologic Complete Response
PubMed: 38778766
DOI: 10.1002/ajh.27343 -
Clinical Epigenetics May 2024Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features....
BACKGROUND
Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.
RESULTS
We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens.
CONCLUSION
We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; DNA Methylation; Female; Male; Prognosis; Middle Aged; Aged; Adult; Rituximab; Aged, 80 and over; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone; Telomere; Antineoplastic Combined Chemotherapy Protocols; Telomere Shortening; Epigenesis, Genetic; CpG Islands
PubMed: 38773655
DOI: 10.1186/s13148-024-01680-4 -
Advances in Rheumatology (London,... May 2024To review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune... (Review)
Review
Position statement of the Brazilian society of Rheumatology on mesna use as a preventive therapy for bladder disease in patients with systemic autoimmune diseases and systemic vasculitis under cyclophosphamide treatment.
OBJECTIVE
To review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide.
MATERIALS AND METHODS
The search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators.
RESULTS
Eighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered.
CONCLUSION
The current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.
Topics: Humans; Cyclophosphamide; Autoimmune Diseases; Cystitis; Mesna; Urinary Bladder Neoplasms; Systemic Vasculitis; Brazil; Immunosuppressive Agents; Hemorrhage; Societies, Medical; Rheumatology
PubMed: 38773538
DOI: 10.1186/s42358-024-00380-0