Dose Of Dexamethasone Research Articles

IMPACT MONITORING OF LOW AND HIGH DEXAMETHASONE DOSES ON COVID-19 OUTCOMES IN HODEIDAH, YEMEN: A PHARMACOEPIDEMIOLOGICAL STUDY

Objectives: The study aimed to describe the pharmacoepidemiological properties of high and low dexamethasone doses on patients from COVID-19 in Hodeidah, Yemen. Methodology: A randomized clinical trial included 192/323 patients with COVID-19 (28/49 cases in the first wave 2020 and 164/274 cases in the second wave 2021), aged from 3 to 80 years old, confirmed by real time-polymerase chain reaction. All patients were admitted in the isolation department, Center of Tropical Medicine and Infectious Diseases, AL Thawara Public Hospital Authority, Hodeidah, Yemen. 28 patients received high dose of dexamethasone (20–10 mg daily for 10 days) with standard care in the first wave and 164 patients received low dose of dexamethasone (6–8 mg daily for 10 days) in the second wave with standard care. Results: The results showed non-significant differences between the impact of dexamethasone in both waves with different doses of dexamethasone (X2: 1.70; p=0.91). On the other mean, the case fatality rate (CFR) in the first wave with high dose was 10.71% and CFR of the second wave with low dose was 22.29%. While the results showed significant differences between high dose and low dose group with mechanical ventilator “mechanical ventilation (MV)” (X2: 7.10; p=0.0076), the CFR of patients with MV and high dose was 37% and CFR of the second wave with low dose was 77% In addition, all admitted cases had acute respiratory distress syndrome and the onset date of symptom was 2 weeks before hospitalization. Old age, chronic diseases, and co-infection may be contributing factors to effect on dexamethasone efficacy and excess mortality among COVID-19 patients. Conclusion: The study assessed the effectiveness of dexamethasone in high and low dose in treating patients hospitalized with COVID-19 in Hodeidah, Yemen and found difference between mortality and recovery outcomes with high and low dose where the high doses of dexamethasone had good outcome for critical cases with MV.

Cellular pathway disturbances elicited by realistic dexamethasone concentrations in gills of mussel Mytilus galloprovincialis as assessed by a multi-biomarker approach

The growing usage of glucocorticoids for a variety of diseases raises concerns since these drugs, including the anti-inflammatory dexamethasone (DEX), are frequently found in the environment. The impact of DEX was evaluated on mussels Mytilus galloprovincialis (Lamarck, 1819) by exposure to environmental concentrations (C1: 4ng/L; C2: 40ng/L; C3: 400ng/L; C4: 2000 ng/L), and sampling at 3 (T3), 6 (T6), and 12 (T12) days. A multi-biomarker approach was applied on gills, involved in gas exchange, feed filtering, and osmoregulation. A dose- and time-dependent uptake of DEX was recorded, besides haemocyte infiltration, increased neutral and acid mucopolysaccharides, and a general pro-oxidant effect witnessed by lipid peroxidation and altered antioxidant system. Metabolomics revealed rise in protein turnover and energy demand by fluctuations in free amino acids (alanine, glycine) and energy-related metabolites (succinate, ATP/ADP). It is necessary to reduce DEX dosage from the environment by recovery strategies and effective eco-pharmacovigilance programs.

Dexamethasone: A simple solution for post-thyroidectomy pain and nausea

Postoperative pain and nausea and vomiting (PONV) are common complications following thyroidectomy. This prospective, double-blind study evaluated the efficacy of a single dose of dexamethasone in mitigating these postoperative adverse effects. Sixty patients undergoing thyroidectomy were randomized into two groups: a dexamethasone group and a control group. The dexamethasone group received a single dose of 8 mg intravenously, while the control group received saline. Postoperative pain was assessed using a visual analog scale (VAS), and PONV was recorded. The results demonstrated that dexamethasone significantly reduced both postoperative pain and the incidence of PONV. These findings suggest that a single dose of dexamethasone is a simple, safe, and effective strategy for improving postoperative outcomes in thyroidectomy patients.

Safety of perioperative intravenous different doses of dexamethasone in primary total joint arthroplasty: a retrospective large-scale cohort study

PurposePerioperative intravenous different doses of dexamethasone (DEX) can realize effective clinical outcomes in total joint arthroplasty (TJA). However, the effect of different DEX doses on readmission rates and postoperative complications remains unclear.MethodsWe retrospectively analyzed patients who underwent primary TJA between December 2012 and October 2020. Patients were categorized into three groups based on the total perioperative dose of DEX: control group (DEX = 0 mg), low-dose group (DEX < 15 mg), and high-dose group (DEX ≥ 15 mg). Primary outcomes included 30-day and 90-day readmission rates. Secondary outcomes included the rates of periprosthetic joint infection (PJI) and wound complications, with treatment outcomes for these complications were also evaluated. Multivariable analysis was used to identify risk factors for readmission.ResultsA total of 14,557 procedures were included, with 6,686 in the control group, 4,325 in the low-dose group, and 3,546 in the high-dose group. No significant differences were observed among the groups for 30-day (p = 0.645) or 90-day readmission rates (p = 0.539). Additionally, there were no significant differences in rates of PJI (p = 0.401) or wound complications (p = 0.079). Treatment for PJI and wound complications was successful across all groups. Risk factors for 30-day readmission included age > 80 years (OR: 2.585, 95% CI: 1.123–5.954, p = 0.026) and undergoing total hip arthroplasty (THA) (OR: 1.692, 95% CI: 1.137–2.518, p = 0.009). For 90-day readmission, age 71–80 years (OR: 2.199, 95% CI: 1.349–3.583, p = 0.002), age > 80 years (OR: 3.897, 95% CI: 1.966–7.727, p < 0.001), and THA (OR: 1.622, 95% CI: 1.179–2.230, p = 0.003) were significant risk factors. However, neither low-dose nor high-dose DEX was associated with increased 30-day or 90-day readmission rates.ConclusionsPerioperative intravenous DEX may be not associated with the readmission, PJI, and wound complications in patients undergoing primary TJA.

Effects of two different dexamethasone dosing regimens on ventilator-free days and long-term mortality in COVID-19 patients with moderate-to-severe ARDS: the REMED randomized clinical trial

BackgroundDexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19.MethodsIn a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1–5, 10 mg/day on days 6–10) or standard-dose dexamethasone (6 mg/d, days 1–10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients.ResultsThe trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5–66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI − 2.12–3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups.ConclusionsDespite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS.Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020–005887-70.

Perioperative intravenous dexamethasone did not reduce the severity of persistent postsurgical pain after total knee arthroplasty: a prospective, randomized, double-blind, placebo-controlled trial

BackgroundEven with the great advancements in recent years in total knee arthroplasty (TKA), some patients continue to have persistent postsurgical pain (PPSP). The advantages of systemic corticosteroids in the perioperative context have been further supported by previously published trials. However, the impact of dexamethasone on the intensity of post-TKA PPSP is still unclear. We aimed to investigate its effect on the degree of PPSP and compare that with a placebo.MethodsIn this randomized, double-blind, placebo-controlled study, 48 patients undergoing unilateral TKA were given intravenous dexamethasone 10 mg or saline just before spinal anesthesia was induced, and they also received two additional doses of dexamethasone 10 mg or saline 24 and 48 h after surgery. A standardized, multimodal analgesic regimen was administered to each patient. The modified WOMAC pain scores at 12 weeks postoperative were the main outcome. The secondary outcomes included pain during a walk of five meters, pain during active knee flexion at 45 degrees, maximum pain at rest during the previous 24 h, nausea visual analogue scale values, and use of rescue opioid and antiemetic medications.ResultsThere was no difference in modified WOMAC pain scores 12 weeks after surgery between patients who received and did not receive perioperative dexamethasone. At 24, 30, 48, 54, and 72 h following surgery, the dexamethasone group experienced considerably less pain during a five-meter walk and during 45 degrees active knee flexion (p < 0.01). At postoperative 0–24, 24–48, and 48–72 h, the dexamethasone group experienced less maximal pain at rest (p < 0.01). The dexamethasone group also had less visual analogue scale scores for nausea at 6, 24, 30, 48, and 54 h after surgery (p < 0.02). During the first 0–24 and 24–48 h, the dexamethasone group consumed fewer opioids and antiemetic medications (p < 0.01). All patients showed no signs of wound complications.ConclusionsWhen compared to a placebo at 12 weeks after TKA, intravenous dexamethasone did not reduce PPSP. Nevertheless, early postoperative pain was relieved by perioperative intravenous dexamethasone, which also decreased the need for opioid and antiemetic medications and decreased postoperative nausea and vomiting.Trial registrationNCT02760459.

Quantifying fluid retention following modern pain management in TKA: an observational study

BackgroundBody fluid retention after major surgeries, including total knee arthroplasty (TKA), is well documented in the literature. Currently, multimodal pain control protocols consisting of several medications together with early discharge protocol may magnify this adverse event after a patient’s discharge. However, no study has focused on the quantitative and chronological changes in body fluids following modern pain management protocols for TKA. The aim of this study was to investigate the perioperative total body water (TBW) change in patient undergoing TKA.Patients and methodsA consecutive series of 85 patients undergoing primary unilateral TKA, with uniform hospital admission, multimodal pain control, and rehabilitation protocol, had five consecutive multifrequency bioelectrical impedance analysis (BIA) scans; baseline, postoperative day 1 (POD 1), postoperative day 3 (POD 3), 2 weeks, and 6 weeks. Changes in TBW, body weight, corticosteroid-fluid retention dose–response relationship, and complications were evaluated.ResultsSeventy patients completed all five scans and follow-ups. Female patients were dominant, with a mean age of 69.5 years. There were no perioperative complications. At 24 h, the mean total fluid input and output were 3695.14 mL and 1983.43 mL, respectively, with 1711.71 mL increments and a mean accumulative dosage of dexamethasone of 15.14 mg. The mean TBW increased by 2.61 L on POD 1 and continued to peak at 3.2 L on POD 3, then gradually decreased at 2 weeks and reached the baseline level at 6 weeks postoperatively. Similarly, the mean body weight increased to 2.8 kg on POD 1, reached the maximum point at 3.42 kg on POD 3, and returned to baseline at 6 weeks.ConclusionsFluid retention following multimodal pain control in TKA increased from POD 1, peaked on POD 3, and gradually returned to the baseline at 6 weeks. With early discharge protocol, patient education regarding fluid retention after discharge should be considered.

Evaluating the Use of Dexamethasone in Diabetic Patients Undergoing Total Joint Arthroplasty: A Systematic Review and Metaanalysis.

The American Association of Hip and Knee Surgeons strongly recommends the use of dexamethasone in patients undergoing total joint arthroplasty due to its therapeutic effects. However, use in diabetic patients is controversial due to safety. Therefore, the objective of this study was to determine safety: (1) calculating the postoperative glucose levels; (2) finding the ideal dexamethasone dosing regimen; and (3) reporting complications of dexamethasone administration in diabetic patients undergoing total joint arthroplasty. A search was performed utilizing the Boolean search phrase "((dexamethasone) AND (diabetic)) AND (((total joint) OR (total knee)) OR (total hip))." Postoperative day (POD) 1, 2, and 3 glucose levels were compared between intervention and control groups with a random-effects proportion meta-analysis weighted for individual study size. Weighted means and SDs were calculated for postoperative glucose levels. Across the 12 studies, 46,685 patients were included, of which 23,892 received at least one dose of dexamethasone. Dexamethasone administration in diabetic patients resulted in significantly elevated mean glucose levels (mg/dL) on POD1 compared to patients in whom dexamethasone was withheld (170.1 ± 5.3 versus 158.1 ± 5.8, P= 0.0007). However, 95% confidence interval levels were below the 200 mg/dL threshold. Additionally, there were no significant differences on POD2 (P= 0.23) and POD3 (P= 0.16). The risk of infection was not significantly different between the intervention and control groups (risk ratio: 0.82, 95% confidence interval: 0.39 to 1.72, P= 0.61). Due to the heterogeneity of data, and only four studies reporting exact dosages as opposed to ranges, an ideal dosage of dexamethasone could not be found. Administration of perioperative dexamethasone in diabetic patients appears to be safe. Further investigation is warranted regarding dosage and timing of administration to optimize beneficial effects of dexamethasone while preventing excessive hyperglycemia in diabetic patients. IV.

The Combination of Intravenous Immunoglobulin, Dexamethasone, and a High Dose of Mononuclear Cells Transfusion: An Effective Strategy for Decreasing Donor-Specific Antibodies During Haploidentical Hematopoietic Stem Cell Transplantation

Donor-specific antibodies (DSAs) are essential causes of graft rejection in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). DSAs are unavoidable for some patients who have no alternative donor. Effective interventions to reduce DSAs are still needed, and the cost of the current therapies is relatively high. In this study, we retrospectively analyzed the data of 11 DSA-positive patients who received haplo-HSCT at our center and evaluated the therapeutic efficacy of the combination of intravenous immunoglobulin (IVIG), dexamethasone and high dose of transfused mononuclear cells (MNCs) for DSA desensitization. The kinetics of DSAs at different times and the engraftment and transplantation outcomes were also observed. We found that all patients had successful donor-cell engraftment and that no patient developed poor graft function. The median engraftment times of neutrophils and platelets were 14 days (range, 11–24 days) and 13 days (range, 11–123 days), respectively. The DSA levels of all patients became negative or dropped under 2000 within 22 days after HSCT. A total of 36.4% of patients developed grade II–IV acute graft-versus-host disease (aGVHD), and 9.1% of patients died of severe gastrointestinal aGVHD. Of the 7 surviving patients, four were diagnosed with chronic GVHD. After a median follow-up of 28.9 months (2.0–52.1 months), four patients died: of relapse (two), aGVHD (one), and multiple-organ failure (one). The 2-year OS, DFS, and NRM were 63.6%, 45.4%, and 18.2%, respectively. Combination therapy with IVIG, dexamethasone, and a high dose of MNCs transfusion, a simple and efficient procedure, was safe and effective for DSA desensitization and peripheral blood stem cell (PBSC) engraftment.

Impact of Therapeutic Doses of Prednisolone and Other Glucocorticoids on Insulin Secretion from Human Islets

Glucocorticoid-induced diabetes (GCID) is a prevalent health issue, generally attributed to insulin resistance. High doses of dexamethasone (DEX) are known to inhibit glucose-stimulated insulin secretion (GSIS), but the effects of lower doses, commonly used in chronic therapy, and equipotent doses of other glucocorticoids (GCs) such as hydrocortisone (HC) and prednisone (PRED) remain underexplored. This study aimed to investigate these effects in vitro, and explore variations between patients. Dynamic perifusion assays were conducted on human islets to evaluate the impact of different GCs on GSIS. The islets were treated for 24h with 250nM PRED and other GCs at equipotent anti-inflammatory doses (HC: 1μM; DEX: 38nM). In 11 human islet donor preparations, 250nM PRED, corresponding to a clinical oral dose of 5mg/day, significantly inhibited the first and second phase of GSIS: area under the curve (AUC) decreased by 32.3% (P<0.001), first phase by 41.5% (P<0.001), and second phase by 38.4% (P<0.001). Despite interindividual differences in GSIS response to PRED, no significant differences were observed according to body mass index, gender or age. Comparing the effects of GCs at equipotent anti-inflammatory doses, DEX had a more pronounced inhibitory effect on GSIS than HC or PRED. In vitro, low-dose PRED treatment significantly impacted GSIS. DEX had a more unfavorable impact on GSIS than HC or PRED, indicating that metabolic effects do not align with anti-inflammatory potency.

Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite

Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: n = 191; 6β-hydroxydexamethasone: n = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.

Efficacy of fosaprepitant for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgery: a multicenter, randomized, double-blind study

PurposeThis study aims to investigate whether adding fosaprepitant to palonosetron and dexamethasone is effective in preventing postoperative nausea and vomiting (PONV) in high-risk patients undergoing gynecologic surgery.MethodsEligible patients undergoing gynecological surgery were randomized into two groups (1:1). One group received fosaprepitant (150 mg) and the other (control) received a placebo infusion. Both groups received a single dose of palonosetron (0.25 mg) and dexamethasone (5 mg) together with therapeutic medication. The primary endpoint was the absence of vomiting and no use of rescue antiemetics during the first 24 h after surgery; complete response rate (CRR).ResultsCRR was significantly higher in the fosaprepitant group compared to the control group 0–24 h after surgery (P = 0.037; relative risk [RR], 1.116; 95% confidence interval [CI], 1.007 to 1.235). Moreover, CRR was also significantly higher during the 24–48 h (P = 0.004; RR, 1.148; 95% CI, 1.045 to 1.261) and 48–72 h (P = 0.039; RR, 1.083; 95% CI, 1.005 to 1.168) observation periods respectively. The complete control rate was higher in the fosaprepitant group than in the control group during the 0–24 h observation period (P = 0.012; RR, 1.367; 95% CI, 1.067 to 1.751). Nausea and rescue antiemetic use were comparable between the two groups. The severity of vomiting was significantly higher in the fosaprepitant group than in the control group on the second day (P = 0.016). Dynamic pain visual analog scale score was lower in the fosaprepitant group and quality of recovery-15 scores were significantly higher in the same group during 0–24 h observation period (P = 0.018 and 0.005, respectively).ConclusionsThe triple combination of fosaprepitant, palonosetron, and dexamethasone was superior in the prevention of PONV after gynecologic surgery in high-risk patients. We suggest that for high-risk patients, a triple combination therapy may be a better choice.Trial registrationRegistered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?proj=171741) with No. ChiCTR2200060890 on June 13, 2022. Principal investigator: Jingdun Xie.

INNV-25. POST-OPERATIVE LOW DOSE VERSUS STANDARD DOSE DEXAMETHASONE FOR MANAGEMENT OF CEREBRAL EDEMA: A RANDOMIZED, DOUBLE-BLINDED FEASIBILITY STUDY IN PATIENTS WITH PRIMARY OR METASTATIC BRAIN TUMORS UNDERGOING CRANIOTOMY FOR TUMOR RESECTION

Abstract INTRODUCTION Although dexamethasone is effective for controlling cerebral edema during the peri-operative period, its immunosuppressive properties can inhibit responses to immunotherapy. We hypothesized that patients with mild to moderate cerebral edema could be safely managed post-operatively with lower doses of dexamethasone. METHODS Eligible patients with brain tumors who had less than 10 mm of midline shift on their pre-operative brain MRIs were randomized 1:1 to the standard or low dose dexamethasone arm, each tapering double blinded through post-op day 8. The double blind was maintained using equivalent volumes for IV doses and capsules containing dexamethasone or placebo. By post-op day 9, participants received the same dose of dexamethasone and continued tapering to off by day 14. Additional doses of dexamethasone were allowed if needed, based on specified symptom criteria. Lack of feasibility was defined as a participant requiring 18 mg or more of dexamethasone in addition to the planned total dose of dexamethasone (low dose: 49 mg; standard dose: 112 mg). Brain MRIs were performed on post-operative days 1, 3, and 8 to evaluate changes in cerebral edema. Manual segmentation and computer-assisted techniques were used to quantitatively measure cerebral edema volume. RESULTS Twenty-six patients were randomized and treated within tumor type strata (primary versus metastatic), of which 25 were evaluable. None of the participants on the low dose dexamethasone arm met the criteria for lack of feasibility. The quantitative assessment of differences in cerebral edema between the arms is ongoing and will be presented. CONCLUSIONS Administration of lower doses of dexamethasone post-operatively to brain tumor patients with mild to moderate cerebral edema is feasible. Treatment with lower doses of dexamethasone post-operatively should be considered in this patient population when peri-operative administration of immunotherapy is planned.

DDEL-17. INTRA-TUMORAL CONVECTION ENHANCED DELIVERY OF DEXAMETHASONE REDUCES INFLAMMATORY SIGNATURES AND EXTENDS SURVIVAL IN GBM MODEL

Abstract Dexamethasone is the most widely utilized drug for glioblastoma (GBM). However, systemic delivery of dexamethasone in GBM patients is associated with significant side effects and increasing doses with worse survival. Convection-enhanced delivery (CED) can deliver high doses of immunotherapy directly into the tumor microenvironment (TME) while avoiding systemic toxicity. Here, we report that high doses of dexamethasone can be delivered locally by CED without side effects and increase survival in a GBM model along with reduced inflammatory myeloid signatures. We investigated CED of dexamethasone treatment on survival(n=40), adverse side effects, and the immunological TME through peripheral analyses, liquid chromatography–mass spectrometry, and histology in a preclinical syngeneic mouse model. Additionally, we assessed the transcriptional responses of human GBM slices and stem-cell-derived human microglia after steroid treatment through bulk and single-cell RNA sequencing. We found that 7-day treatment with CED of dexamethasone produced a significant survival advantage in glioma-bearing mice compared to non-treated control(p=0.03). Systemic dexamethasone achieved low levels of drug in the TME and caused dysregulated blood glucose, blood counts, and peripheral organ weights, while high CED doses avoided these side effects(p&amp;lt; 0.05 each). Steroid treatment of acute GBM slices and lipopolysaccharide-activated microglia in-vitro both reversed inflammatory myeloid signatures associated with poor survival and recurrence on RNA sequencing analyses. We demonstrate the preclinical efficacy of delivering high local doses of dexamethasone in a GBM model through CED and observed prolonged survival along with reduced adverse inflammatory myeloid signatures. No side effects were demonstrated after chronic CED treatment of dexamethasone while systemic delivery achieved poor tumor penetration and caused known hematologic and metabolic side effects supporting the potential to optimize the clinical use of this therapy. CED of dexamethasone provides us a new treatment paradigm to locally control inflammatory signatures in the glioma TME in a controlled fashion.

CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS

Abstract BACKGROUND Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). METHODS Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion. RESULTS Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis. CONCLUSIONS Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.

First-choice hormonal therapies for children with infantile epileptic spasms syndrome in South Asia: A network meta-analysis of randomized controlled trials.

Considering the peculiar challenges with infantile epileptic spasms syndrome (IESS) in South Asia and a wide variation in the usage of hormonal therapies, we compared the efficacy and safety of various hormonal therapies for children with IESS in South Asia. We searched PubMed, Embase, Scopus, and Web of Science databases from the inception until April 2024. We included only randomized clinical trials (RCTs) evaluating the efficacy and safety of hormonal therapies for IESS in the South Asian region. Complete cessation of epileptic spasms (ES), electro-clinical response, and time taken to be spasm-free at 2 or 6 weeks of therapy were efficacy outcomes, while the occurrence of adverse events was the safety outcome. Effect estimates were reported as odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CI) and Cochrane risk of bias 2.0 (ROB 2.0) used for quality assessment of each study. The surface under the cumulative ranking curve (SUCRA) was used to rank the different therapies and reported as a p-score ranging from 0 to 1. Of 747 citations, nine RCTs comprising 566 children with IESS were included. After 2-week treatment, dexamethasone (OR: 6.72; 95% CI: 1.47, 30.72), adrenocorticotropic hormone therapy (ACTH) high dose (HD) (OR: 5.30; 95% CI: 1.05, 26.91), and prednisolone HD (OR: 2.41; 95% CI:1.07, 5.46) had shown significantly greater efficacy for cessation of EScompared with ACTH low dose (LD). Similarly, for electroclinical response, dexamethasone (OR: 9.63; 95% CI: 1.99, 46.70) and prednisolone HD (OR: 3.46; 95% CI: 1.38, 8.68) had greater efficacy compared with ACTH LD. Safety outcomes revealed that hypertension was significantly less common with ACTH LD and prednisolone HD as compared with ACTH HD. This study provides quality evidence on preferred first-choice hormonal therapy for managing IESS in South Asia. ACTH HD, dexamethasone, and prednisolone HD are the most effective hormonal therapy options with dose-dependent therapeutic efficacy. PLAIN LANGUAGE SUMMARY: This study provides insights into the selection of first-line hormonal therapies among the various treatments for managing infantile epileptic spasms syndrome (IESS) in South Asia. The study findings suggested that the effectiveness of these therapies is dose-dependent, with high doses of ACTH, dexamethasone, and prednisolone being the most effective for achieving cessation of epileptic spasms.

A Phase 1b, Dose Escalation/Dose Expansion, Multicenter, Open-Label Study to Assess the Safety and Tolerability of OPN-6602 Monotherapy and in Combination with Dexamethasone in Subjects with Relapsed and/or Refractory Multiple Myeloma

Background and Significance: OPN-6602 is a potent, selective, and orally active small molecule dual cyclic-AMP response element-binding protein (CBP) and E1A binding protein (EP300) bromodomain (BRD) inhibitor. It has low nanomolar potency against EP300 and CBP, with greater than 100-fold less activity against BRD3, which was the most potent among all the other BRDs evaluated. OPN-6602 suppresses known oncogenes interferon regulatory factor 4 (IRF4) with downstream suppression of MYC resulting in antitumor activity through EP300/CBP inhibition. It is a potent inhibitor of multiple myeloma (MM) cell growth in the MM cell lines, OPM-2 and MM.1S, and a potent inhibitor of histone acetylation via BRD intramolecular modulation of histone acetyltransferase (HAT) activity. EP300 and CBP are transcription coactivators that contain both epigenetic writer HAT and reader BRDs that regulate transcription of genes via chromatin remodeling. EP300 and CBP are highly conserved and ubiquitously expressed enzymes that belong to the KAT3 family of acetyltransferases. EP300 and CBP interact with numerous other proteins to function as global transcriptional coactivators through the modification of lysines on both histone and non-histone nuclear proteins, affecting proteins such as IRF4 and MYC. IRF4/MYC act as lineage-specific transcription factors controlling the survival and growth of MM. EP300/CBP inhibition causes cell cycle arrest and apoptosis in MM through suppression of IRF4 and MYC, rendering EP300/CBP as a novel target for MM (Conery 2016). Recently, unbiased analysis of vulnerability genes identified EP300 as a specific and highly relevant target for MM (de Matos Simoes 2023). OPN-6602 pharmacokinetic (PK) studies in mice, rats, and dogs consistently showed moderate clearance and short terminal half-life. In definitive 28-day GLP toxicology studies, OPN-6602 showed near dose-proportional increases in exposure over the dose range evaluated. These PK properties were specifically engineered to enable daily ‘pulsatile’ dosing. The potent selective inhibition of EP300 and CBP can be exploited to address several unmet medical needs through different mechanisms. In particular, a selective inhibitor of EP300 and CBP such as OPN-6602 has the potential to be a promising treatment for MM. Study Design and Methods: Study OPN6602-C01 is a Phase 1b, open-label study evaluating the safety, tolerability, PK, preliminary antitumor activity, and pharmacodynamics of OPN-6602 monotherapy and in combination with dexamethasone in subjects with relapsed and/or refractory MM. OPN-6602 as monotherapy or in combination with dexamethasone will be administered orally once daily in 21-day cycles. This study consists of 3 parts: Part 1a OPN-6602 monotherapy dose escalation (Part 1a), Part 1b OPN-6602 combination with dexamethasone dose escalation (Part 1b), and Part 2 dose expansion of the preferred regimen (Part 2) to select and optimize the dose with 1:1 randomization of at least 2 potential dose levels of 20 subjects at each dose level (ie, the provisional recommended Phase 2 dose [RP2D] identified in Part 1a or Part 1b and 1 additional dose level). Either OPN-6602 monotherapy or OPN-6602 in combination with dexamethasone will be selected for Part 2. Up to 130 total evaluable subjects will be enrolled across dose escalation and dose expansion. The primary objective and endpoint for Part 1a and Part 1b is to characterize the tolerability of OPN-6602 (with and without dexamethasone). Dose limiting toxicities, treatment-emergent adverse events and changes in safety and lab parameters will be characterized in order to identify the RP2D. The primary objective and endpoint for dose expansion of OPN-6602 monotherapy or in combination with dexamethasone is to evaluate the preliminary antitumor activity using overall response rate based on the 2011 International Myeloma Working Group (IMWG) response criteria. Eligibility criteria include a confirmed diagnosis of MM per IMWG criteria, disease that is relapsed or refractory to 3 or more different prior lines of therapy that include immunomodulatory agents, proteasome inhibitors and an anti-CD38 antibody, measurable disease and adequate hematologic, renal and liver function. This multi-center study (NCT06433947) is currently open in the United States with additional sites planned to open in Switzerland, United Kingdom and the European Union.

Timing of Dexamethasone Initiation and Its Impact on the Outcome of COVID-19 Patients.

Introduction COVID-19 emerged in Wuhan in December 2019 and was declared a pandemic in March 2020. Severe cases manifest with respiratory distress. Corticosteroids, initially debated, are now recommended for severe cases following the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial findings. The timing of administration impacts outcomes, with earlier use potentially improving mortality and ICU stays. Regional studies on timing in severe cases are lacking, warranting further investigation. Methodology This retrospective cohort study was conducted at the Medical Department of King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. Data were extracted from the BestCare database using a customized data collection sheet. Data were cleaned in Excel (Microsoft Corporation, Redmond, WA) and analyzed in IBM SPSS (IBM Corp., Armonk, NY). Results Our study included 791 COVID-19 patients with 43.1% being female (n = 341) and 56.9% being male (n = 450). The mean age was 69.5 years (SD = 16.1). Regarding BMI, 52.4% (n = 414) were obese. Most admissions were from the emergency department (90.6%, n = 717). Dexamethasone was administered to 80.3% (n = 635) of patients, with 53.0% (n = 419) receiving it early. Patients receiving early dexamethasone had significantly higher discharge rates (p < 0.001). Mortality was higher among those receiving late dexamethasone initiation (52.6%, p = 0.256). Moreover, there was an 87.5% death rate for doses >6 mg (p < 0.001). Intravenous administration was associated with higher mortality (62.3%, p < 0.001). Males had a higher likelihood of discharge (OR = 1.426, p= 0.043). Age and ventilation needs were strong mortality predictors (OR = 1.040, p < 0.001 and OR = 17.620, p < 0.001, respectively). Higher BMI slightly reduced mortality risk (OR = 0.978, p = 0.049). Conclusion Our study highlights significant associations between dexamethasone timing, dosage, and route of administration with COVID-19 outcomes. Early dexamethasone use correlated with higher discharge rates, while late initiation and higher doses were linked to increased mortality. Age and ventilation needs were critical predictors, with BMI showing a nuanced effect on mortality risk.

Dexamethasone regime and clinical outcomes in children hospitalized with croup: A cohort study.

High-quality trial evidence supports the use of one dose of dexamethasone in the outpatient management of croup; however, there are no inpatient trials, and the optimal treatment regimen for the inpatient management of croup remains uncertain. Significant practice variability exists in the corticosteroid treatment of children hospitalized for croup. To evaluate the association of dexamethasone treatment regimen (1 vs. >1 dose) with hospital length of stay (LOS) and 30-day return to emergency department (ED) visits among children hospitalized for croup. A cohort study of children hospitalized for croup at a children's hospital between 2010 and 2022. Children less than 10 years old, without known airway anomalies and who received dexamethasone for croup treatment were included. Children who received 1 dose versus >1 dose of dexamethasone were compared. Propensity score analyses, using inverse probability of treatment weighting, were conducted to estimate the treatment effects of dexamethasone regimen on hospital LOS and all-cause 30-day return to ED visit. Of 471 children hospitalized for croup, 229 (49%) received 1 dose of dexamethasone; 242 (51%) received >1 dose. In the propensity-weighted analyses, children receiving >1 dose of dexamethasone had a longer mean LOS by 59.6 h (95% CI 44.8-74.5, p < .001) compared with those receiving >1 dose. There was no statistically significant difference in the odds of all-cause 30-day return to ED visit; OR 1.30, (95% CI 0.76-2.22, p = .33). Among children hospitalized for croup, children who received >1 dose of dexamethasone had a longer LOS compared with children who received 1 dose of dexamethasone; however, there was no statistically significant difference in the 30-day return to ED visits. Randomized clinical trials are needed to determine the optimal dexamethasone treatment regimen for children hospitalized with croup.

Targeted therapy of multiple myeloma by IL21-NKG2D CAR-T cells.

NKG2D chimeric antigen receptor (CAR)-modified T cells (NKG2D CAR-T cells) have been reported to be preclinically efficient in several tumors, but little is known whether NKG2D CAR-T cells co-expressing IL21 (IL21-NKG2D CAR-T cells) display greater antitumor activity in multiple myeloma (MM). In this study, the lentivirus has been produced for expression of the IL21 sequence linked to the extracellular NKG2D sequence with the signal peptide linked through the CD8α hinge-transmembrane domain to the 4-1BB molecule fused with the CD3-ζ chain signaling domain, and the engineered IL21-NKG2D CAR-T cells and NKG2D CAR-T cells were constructed. The CAR expression on CAR-T cells was assessed by flow cytometry, and the killing effects of CAR-T cells on MM were assessed by the cytotoxicity assay and ELISA assay. Moreover, xenograft models were also established to evaluate the ability of IL21-NKG2D-CAR-T cells to eliminate MM in vivo. Our results indicated that NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro, and co-expression of IL-21 significantly increased the cytotoxicity of NKG2D CAR-T cells on MM cells. Remarkably, we found that dexamethasone enhanced the cytotoxicity of IL21-NKG2D CAR-T cells on MM cells. Furthermore, IL21-NKG2D CAR-T cells also displayed significant anti-myeloma activity in vivo. In conclusion, IL21-NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro and in vivo, and a system to apply IL21-NKG2D CAR-T cells and low dosage of dexamethasone for the future study of the targeted therapy for MM has been established.