Dose Of Dexamethasone Research Articles

Postoperative analgesic effects of intravenous dexamethasone for patients undergoing cesarean delivery under spinal anesthesia at Dilla University Referral Hospital, Ethiopia, 2023: a double-blind randomized controlled trial.

The use of cesarean section (CS) worldwide has increased to unprecedented levels. In Ethiopia, the CS delivery rate is above the rate recommended by the WHO. The postoperative pain experience is moderate to severe in most patients during their postoperative period. The administration of intravenous dexamethasone is thought to have an analgesic effect after surgery even though the analgesic profile of preoperatively administered dexamethasone is less addressed. This study aimed to assess the postoperative analgesic effect of preoperative intravenous dexamethasone for patients undergoing cesarean delivery under spinal anesthesia at Dilla University Referral Hospital, Southern Ethiopia. A double-blinded randomized controlled trial (RCT) was done on 112 patients undergoing elective CS under spinal anesthesia who were allocated randomly into normal saline and dexamethasone groups. Total analgesic consumption, time to first analgesic request, and postoperative pain score with the numerical rating scale (NRS) were followed for 24 h in both groups. Shapiro-Wilk tests were used to check normality. Independent samples t-test was used for the comparison of means between groups, Mann-Whitney U test for non-normally distributed data, and χ 2 test for categorical variables, and P-value <0.05 was considered statistically significant with a power of 80%. The finding of this study showed that the postoperative pain score of the dexamethasone group was significantly lower than the normal saline group at 2, 4, 6, 12, 18, and 24 h with a statistically significant P-value <0.05. There was also a significant difference in the time to the first rescue analgesic request between the two groups, with the dexamethasone group (median=347.5 min) and the normal saline group (median=230 min) with P=0.001. The authors conclude that preoperative administration of 8 mg of dexamethasone prolongs the first analgesic request time, decreases postoperative tramadol and diclofenac consumption, and decreases the postoperative pain score. The authors recommend that researchers conduct further RCTs with a different dose of dexamethasone and on a multicenter basis.

Should intravitreal dexamethasone implant in refractory diabetic macular edema be used as an adjuvant therapy or switch therapy?

To compare the outcomes of intravitreal dexamethasone implant used as either an adjuvant or a switching therapy for diabetic macular edema in patients with poor anatomic response after three consecutive monthly injections of ranibizumab. This retrospective study included patients with diabetic macular edema who received three consecutive doses of ranibizumab as initial therapy and demonstrated poor response. A single dose of intravitreal de xamethasone implant was administered to these patients. The patients were divided into two groups according to the treatment modalities: the adjuvant therapy group, consisting of patients who continued treatment with ranibizumab injection after receiving intravitreal dexamethasone implant, and the switch therapy group, consisting of patients who were switched from ranibizumab treatment to intravitreal dexamethasone implant as needed. The main outcome measurements were best corrected visual acuity and central retinal thickness at baseline and at 3, 6, 9, and 12 months of follow-up. In this study that included 64 eyes of 64 patients, the best corrected visual acuity and central retinal thickness values did not significantly differ between the groups at baseline and at 6 months of follow-up (p>0.05). However, at 12 months, the best corrected visual acuity values in the adjuvant and switch therapy groups were 0.46 and 0.35 LogMAR, respectively (p=0.012), and the central retinal thickness values were 344.8 and 270.9, respectively (p=0.007). In a real-world setting, it seems more reasonable to use intravitreal dexamethasone implant as a switch therapy rather than an adjuvant therapy for diabetic macula edema refractory to ranibizumab despite three consecutive monthly injections of ranibizumab. Patients switched to intravitreal dexamethasone implant were found to have better anatomic and visual outcomes at 12 months than those who continued ranibizumab therapy despite their less-than-optimal responses.

Acute suppression of the hypothalamo-pituitary-adrenal axis from a large singular dose of dexamethasone: A case report on a hypothesis for resistant intraoperative hypotension.

Acute suppression of the hypothalamo-pituitary-adrenal axis from a large singular dose of dexamethasone: A case report on a hypothesis for resistant intraoperative hypotension.

Dexamethasone-sparing strategies in anthracycline and cyclophosphamide-based chemotherapy with a focus on 5-HT3 receptor antagonists: a network meta-analysis.

The effectiveness of a dexamethasone-sparing strategy in the treatment of breast cancer with anthracycline-cyclophosphamide therapy when combined with first-generation 5-HT3 receptor antagonists (RAs) and neurokinin-1 RAs is unclear. This is attributable to a lack of evidence from direct comparison of multiple doses of DEX to a single dose of DEX in combination with first-generation 5-HT3 RAs in anthracycline-cyclophosphamide therapy. Our goal was to clarify the impact of dexamethasone-sparing strategies that involve both first-generation 5-HT3 RAs and palonosetron when combined with neurokinin-1 RAs, using a network meta-analysis. A literature search was conducted on PubMed/Medline for articles published up to July 4, 2023. We included randomized controlled trials which assessed the efficacy of antiemetic regimens which combined 5-HT3 RAs and dexamethasone, with or without neurokinin-1 RAs, for the initial dose in anthracycline-cyclophosphamide therapy for patients with breast cancer. The primary outcome was the proportion of patients achieving a complete response during the delayed phase (CR-DP). The difference in the proportion of patients achieving CR-DP between multiple and single doses of dexamethasone was 0.1% (95%CI: -12.4 to 12.5) with palonosetron and neurokinin-1 RAs, compared to 5.3% (95%CI: -13.4 to 23.0) with a single dose of a first-generation 5-HT3 receptor antagonist. Additionally, the difference was 12.7% (95% CI: -2.8 to 28.2) when comparing palonosetron against first-generation 5-HT3 RAs in combination with a single dose of dexamethasone and neurokinin-1 RAs. Palonosetron is recommended rather than a single dose of first-generation 5-HT3 RAs in dexamethasone-sparing strategies for anthracycline-cyclophosphamide therapy.

Optimal initial insulin dosage for managing steroid-induced hyperglycemia in hospitalized COVID-19 patients: A retrospective single-center study.

To determine the optimal initial insulin dosage for controlling hyperglycemia in COVID-19 patients receiving steroids, an area with limited data. We retrospectively analyzed 156 COVID-19 patients with steroid-induced hyperglycemia treated with insulin. Patients were categorized by their total daily dose of subcutaneous insulin therapy when starting dexamethasone ⩾6 mg/day or equivalent dose of glucocorticoid: Group A (⩽0.29 units/kg), Group B (0.3-0.49 units/kg), Group C (0.5-0.69 units/kg), and Group B (⩾0.7 units/kg). Treatment failure was defined as mean blood glucose level > 280 mg/dL for two consecutive days after initiating insulin or any blood glucose ⩾ 400 mg/dL. The mean age was 64 ± 14 years, with 50% male, and a mean body mass index of 26.9 ± 6.9 kg/m2. Most had preexisting type 2 diabetes (62%). Mean admission blood glucose and HbA1c were 233 ± 112 mg/dL and 7.8 ± 2.3%, respectively. Group A had the lowest HbA1c (6.7 ± 1.2%), while group D had the highest (9.8 ± 2.5%). Median daily dexamethasone dosage or equivalent was 36 (IQR 16.72) mg, with no significant differences in among groups. Group A had the lowest treatment failure rate. There were no significant differences in treatment failure rate between Groups B, C, and D. Additionally, there were no statistically significant differences in mean BG across the groups: Group A 232 ± 42 mg/dL, Group B 247 ± 57 mg/dL, Group C 247 ± 61 mg/dL, and Group D 227 ± 67 mg/dL (p = 0.2). Group D had a significantly higher rate of level 1 hypoglycemia (p = 0.008), while no differences in clinically significant hypoglycemia (level 2 or 3) were observed between groups. Among patients requiring TDD ⩾ 0.3 units/kg/day, there was no significant difference in treatment failure rate between Groups B, C, and D. Group D had the highest rate of level 1 hypoglycemia. This initial insulin dosage for hospitalized COVID-19 patients on high-dose steroid therapy should be personalized.

QUİNCKE DİSEASE İN EARTHQUAKE ZONE

Quincke's Disease or isolated uvular angioedema was described in 1882 by German physician Heinrich Quincke. It is a rare angioedema that only affects the upper airway.[1] It is characterized by swelling of the uvula, which rests on the tongue.When I worked in an earthquake zone, there were 2 Quincke's disease applications within a month. Two men, aged 37 and 41, were the patients. They applied to the emergency room with a complaint of foreign body swelling in the throat.There was no fever on physical examination in both of them. Respiratory rate, blood pressure, heart rate, and oxygen saturation were normal. Both were conscious, GKS 15, oriented and cooperative. There was no exposure to any allergens or medication use. No allergy-triggering factor could be identified in their history.They did not have any disease. It was learned that one of them had previously had the same attack on Mount Ararat, while the other patient had the first attack in his life. After 2 repeated doses of dexamethasone (8 mg), chlorpheniramine maleate and inhaled corticosteroid treatment, the patients' uvula edema resolved. Epinephrine was not administered to both patients. After eight hours of follow-up, they were discharged with a completely normal physical examinationThe fact that we encountered 2 cases of Quincke edema, a rare allergic reaction, within 1 month in a district public hospital with a low number of daily patient admissions in the period after the earthquake, made us think that asbestos and other substances that increased after the earthquake could trigger Quincke edema.

Effect of dexamethasone on antibody response of horses to vaccination with a combined equine influenza virus and equine herpesvirus-1 vaccine.

Dexamethasone is routinely administered to horses but its effect on the antibody response to a commercial EIV/EHV vaccine is unclear. Horses receiving dexamethasone will have lower postvaccination antibody levels against EIV and EHV-1 than vaccinated controls. Fifty-five healthy adult research horses. Randomized cohort study. Control (no vaccine, group 1), vaccination only (EIV/EHV-1/EHV-4, Prestige 2, Merck Animal Health, group 2), vaccination and concurrent single intravenous dose of dexamethasone (approximately .05 mg/kg, group 3), vaccination and 3 intravenous doses of dexamethasone at 24 hours intervals (group 4). Serum SAA levels were measured on day 1 and day 3. Antibody levels against EIV (hemagglutination inhibition assay, Kentucky 2014 antigen) and EHV-1 (multiplex ELISA targeting total IgG and IgG 4/7) were measured on day 1 and day 30. Significantly increased mean antibody titers after vaccination were only noted against EIV and only after the vaccination alone (n = 14, prevaccine mean [prvm] 166.9, SD 259.6, 95% CI 16.95-316.8; postvaccine mean [povm] 249.1, SD 257.2, 95% confidence interval [CI] 100.6-397.6, P = .02) and the single dose dexamethasone (n = 14, prvm 93.14, SD 72.2, CI 51.45-134.8; povm 185.1, SD 118, CI 116.7-253.6, P = .01), but not after multiple doses of dexamethasone (n = 14, prvm 194.3, SD 258.3, CI 45.16-343.4; povm 240.0, SD 235.7, CI 103.9-376.1, P > .05). The effect of dexamethasone on the postvaccine antibody response varies depending on the dosing frequency and the antigen-specific antibody type.

Effects of phospholipids from embryonated egg yolk on lipopolysaccharide-induced acute lung injury by regulating the serum metabolism

Acute lung injury is a severe and intricate condition characterized by the disruptions in the alveolar barrier, pulmonary edema, enhanced inflammation, and alveolar apoptosis. Existing therapeutic approaches often exhibit limited efficacy and undesirable side effects. Egg yolk phospholipids have shown some potential as nutritional supplements due to their anti-apoptotic and anti-inflammatory properties under various conditions. This study aimed to explore whether phospholipid supplementation, particularly those rich in phosphatidylcholine, could alleviate lipopolysaccharide-induced lung injury in mice. Mice received daily oral administrations of phospholipid extracts (800 mg/kg) from different sources (embryonated egg yolk on day 18 and unfertilized fresh egg yolk) for 7 days or a single dose of dexamethasone (positive control). Subsequently, lipopolysaccharide (10 mg/kg) was intraperitoneally injected, and the mice were euthanized after 6 h. Various samples were collected for histological examination, assessment of inflammation and oxidative stress, serum metabolome analysis, and identification of gut flora. Results demonstrated that pretreatment with phospholipids effectively mitigated damages to the alveolar-capillary barrier and reduced lung edema by suppressing the release of oxidative and inflammatory cytokines, with embryonated egg extracts exhibiting superior efficacy. Additionally, the protective mechanism of phospholipids seemed associated with the metabolic distribution and absorption, helping to maintain the right lipid metabolism and restore protein synthesis, thus mitigating the impact of lung injury. In conclusion, supplementation with phosphatidylcholine-enriched phospholipids may serve as an innovative nutritional strategy to alleviate the adverse effects of bacterial infection on alveolar function.

Impact of a discharge prescription for dexamethasone on outcomes of children treated in the emergency department for acute asthma exacerbations

Objective To evaluate dexamethasone prescribing practices, patient adherence, and outcomes by dosing regimen in children with acute asthma discharged from the emergency department (ED). Study design Prospective study of children 2–18 years treated with dexamethasone for acute asthma prior to discharge from an urban, tertiary care ED between 2018 and 2022. Demographics, clinical characteristics, ED treatment, and discharge prescriptions were collected via chart review. The exposure was discharge prescription (additional dose) versus no discharge prescription for dexamethasone. The primary outcome was treatment failure, defined as return ED visit, unplanned primary care visit, and/or ongoing bronchodilator use. Secondary outcomes included medication adherence, symptom persistence, quality-of-life, and school/work absenteeism. Outcomes were assessed by telephone 7–10 days after discharge. Results 564 subjects were enrolled; 338 caregivers (60%) completed follow-up. Children were a median age 7 years, 30% Black or African American, 49% Hispanic, and 79% had public insurance. A discharge prescription for dexamethasone was written for 482 (86%) children and was significantly associated with exacerbation severity, number of combined albuterol/ipratropium treatments, and longer length of stay. There was no difference in treatment failure between the discharge prescription and no discharge prescription groups (RR 0.87; 0.67, 1.12), including after adjusting for potential confounders; there was no difference between groups in secondary outcomes. Conclusions Prescription for an additional dexamethasone dose was not associated with reduced treatment failure or improved outcomes for children with acute asthma discharged from the ED. Single, ED-dose of dexamethasone prior to discharge may be sufficient for children with mild to moderate asthma exacerbations.

556: ASSOCIATION OF DEXAMETHASONE DOSING WITH OUTCOMES AMONG PATIENTS WITH COVID-19

556: ASSOCIATION OF DEXAMETHASONE DOSING WITH OUTCOMES AMONG PATIENTS WITH COVID-19

Postnatal steroids as lung protective and anti-inflammatory in preterm lambs exposed to antenatal inflammation.

Lung inflammation and impaired alveolarization precede bronchopulmonary dysplasia (BPD). Glucocorticoids are anti-inflammatory and reduce ventilator requirements in preterm infants. However, high-dose glucocorticoids inhibit alveolarization. The effect of glucocorticoids on lung function and structure in preterm newborns exposed to antenatal inflammation is unknown. We hypothesise that postnatal low-dose dexamethasone reduces ventilator requirements, prevents inflammation and BPD-like lung pathology, following antenatal inflammation. Pregnant ewes received intra-amniotic LPS (E.coli, 4 mg/mL) or saline at 126 days gestation; preterm lambs were delivered 48 h later. Lambs were randomised to receive either tapered intravenous dexamethasone (LPS/Dex, n = 9) or saline (LPS/Sal, n = 10; Sal/Sal, n = 9) commencing <3 h after birth. Respiratory support was gradually de-escalated, using a standardised protocol aimed at weaning from ventilation towards unassisted respiration. Tissues were collected at day 7. Lung morphology and mRNA levels for inflammatory mediators were measured. Respiratory support requirements were not different between groups. Histological analyses revealed higher tissue content and unchanged alveolarization in LPS/Sal compared to other groups. LPS/Dex lambs exhibited decreased markers of pulmonary inflammation compared to LPS/Sal. Tapered low-dose dexamethasone reduces the impact of antenatal LPS on ventilation requirements throughout the first week of life and reduces inflammation and pathological thickening of the preterm lung IMPACT: We are the first to investigate the combination of antenatal inflammation and postnatal dexamethasone therapy in a pragmatic study design, akin to contemporary neonatal care. We show that antenatal inflammation with postnatal dexamethasone therapy does not reduce ventilator requirements, but has beneficial maturational impacts on the lungs of preterm lambs at 7 days of life. Appropriate tapered postnatal dexamethasone dosing should be explored for extuabtion of oxygen-dependant neonates.

Progressive shingles in a toddler due to reactivation of Varicella Zoster vaccine virus four days after infection with SARS-CoV-2; a case report

BackgroundHerpes zoster (HZ) is the clinical syndrome associated with reactivation of latent varicella-zoster virus (VZV). Several factors have been implicated to promote VZV reactivation; these include immunosuppression, older age, mechanical trauma, physiologic stress, lymphopenia, and more recently, infection with severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2). Recent reports suggest an increase in the number of HZ cases in the general population during the global COVID-19 pandemic. However, it is unknown what proportion of HZ during the pandemic is due to reactivation of wild-type or vaccine-strain VZV.CaseHere we report the first known case of HZ concomitant with SARS-CoV2 infection in a 20-month-old female who was treated with a single dose of dexamethasone, due to reactivation of the vaccine-type strain of VZV after presenting with a worsening vesicular rash.ConclusionIn this case, we were able to show vaccine-strain VZV reactivation in the context of a mild acute symptomatic COVID-19 infection in a toddler. Being able to recognize HZ quickly and effectively in a pediatric patient can help stave off the significant morbidity and mortality associated with disease process.

A physiologically based toxicokinetic model of P-glycoprotein transporter-mediated placenta perfusion of dexamethasone in the pregnant rat

The present dosage of Dexamethasone (DEX) administered to pregnant women may pose a risk of toxicity to their unborn offspring. We aimed to develop a maternal-fetal physiologically based toxicokinetic (PBTK) model for DEX in pregnant rats, with a specific focus on the role of the P-glycoprotein (P-gp) transporter in placenta perfusion, and finally facilitate the optimization of clinical DEX dosage. We conducted animal experiments to determine DEX concentrations in various rat tissues, and constructed the PBTK model using MATLAB software. Sensitivity analysis was performed to assess input parameters and the model stability, with fold error (FE) values serving as evaluation indices. Our results indicate the successful construction of the PBTK model, with the fitting key parameters such as the absorption rate constant (Ka), intrinsic hepatic clearance (CLh,int) and intrinsic P-gp clearance (CLint,P-gp). The median concentration of DEX in maternal plasma, fetal plasma, fetal lung, and fetal brain were determined, which allowed us to fit the tissue-to-plasma partition coefficients for the fetal lung (Kp,lung,f) and fetal brain (Kp,brain,f). After making adjustments, all calculated FE values were found to be less than 2, demonstrating the acceptability and accuracy of our model's predictions. Our model integrated external literature data and internal animal experimentation to comprehensively evaluate the maternal-fetal PK characteristics of DEX. These findings provide valuable support for the optimization of clinical DEX dosing.

Evaluation of Dexamethasone Dosing Strategies in Pediatric Asthma Exacerbations

OBJECTIVES This study aimed to determine if there is a difference in health care use in pediatric asthma exacerbations with dexamethasone at a standardized dose compared with a weight-based approach. METHODS This was a single-center, retrospective study of patients ages 2 to 17 years presenting to the pediatric emergency department (ED) with an asthma exacerbation between July 1, 2018, and June 30, 2021. Patients who received at least 1 dose of dexamethasone and had an International Classification of Diseases, 10th revision (ICD-10) code for asthma were included. The primary end point was the rate of return visits to the ED within 30 days and 31 to 90 days. Secondary end points included incidence of hospitalization and intubation, length of stay, dexamethasone dosing discrepancies, other corticosteroids or adjunctive therapies used, and medication escalation at discharge. The incidences of vomiting, hyperglycemia, and hypertension were also evaluated. Descriptive statistics were used for categoric variables and a Kaplan-Meier survival curve and Cox regression evaluated the primary outcome. RESULTS A total of 252 patients were included, 162 in the standardized dosing group and 90 in the weight-based group. There was no difference in return visits at 30 days and 31 to 90 days (3.1 vs 4.4, p = 0.58; and 3.7 vs 7.8, p = 0.16). The standardized group had a statistically significant shorter length of stay and lower ipratropium and magnesium use compared with the weight-based group. However, hospitalization rates were lower overall in the weight-based group. The incidences of vomiting, hyperglycemia, and hypertension were similar. CONCLUSIONS A standardized dosing strategy for dexamethasone in pediatric asthma exacerbations showed favorable outcomes and may lead to improved adherence.

Retrospective Evaluation of a Dexamethasone Sparing Antiemetic Regimen: An Antiemetic Prophylaxis Study on NEPA (Netupitant Plus Palonosetron) for Preventing Chemotherapy-Induced Nausea and Vomiting (CINV) in Cancer Patients.

Background Corticosteroids, specifically dexamethasone (DEX), have been extensively utilized for the prevention of chemotherapy-induced nausea and vomiting (CINV). However, their usage is associated with a range of adverse events. In contrast, the combination of NetupitantPlus Palonosetron (NEPA) with a single dose of DEX provides comparable efficacy in preventing CINV over a five-day period following chemotherapy administration. This regimen offers the advantage of reducing the need for additional doses of DEX, particularly in the high-risk setting of HEC (Highly emetic chemotherapy). Objective To evaluate dexamethasone sparing anti-emetic regimen (single dose dexamethasone with NEPA) for prophylaxis of CINV in patients receiving HEC. Methodology This is a retrospective, observational, real-world, single-center study including data of 69 patients who received high-dose emetogenic chemotherapy and were administered DEX (8 or 12 mg) on day 1, with no dose ofDEX on days 2, 3, and 4, combined with an oral combination of tablet netupitant 300 mg and palonosetron 0.5 mg. NEPA was taken orally an hour prior to the start of the HEC cycle. The primary efficacy endpoint was complete response (CR) which is defined as no nausea, emesis, or no rescue medication during the Acute (< 24 hours) and Delayed Phase (25-120 hours) of chemotherapy. Results The overall CR achieved in the acute and delayed phase for vomiting is 100% at all four follow-ups. The CR achieved in the acute phase is 95.7% whereas 98.6% of patients showed CR in the delayed phase respectively. No patient required any rescue medication. No acute and delayed phase of vomiting was reported. Conclusion A simplified regimen of NEPA plus single-dose DEX offers effective CINV prevention throughout five days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting chemotherapy.

Enhanced T Cell Function of PTPN2 Deleted CAR-T Cells Comes at a Cost: PTPN2 Knockout CAR-Ts Secrete More Cytokines and Demonstrate Increased Cytotoxicity, but Exhibit More Severe CRS and Icans in a Non-Human Primate Model

Background: Despite the success of CD19 CAR-T cells (CAR-Ts) in inducing remission, relapse remains a major issue. Previous studies have shown that upregulation of negative T cell regulators can contribute to CAR-T failure, and that deletion of these regulators can enhance CAR-T efficacy. A potent negative regulator is PTPN2, which inhibits T cell function by modulating T cell receptor and cytokine signaling pathways. While murine models have shown that PTPN2-knockout T cells improve tumor control, these models fail to reliably predict clinical efficacy or toxicity. To improve this predictability, we investigated PTPN2 KO CAR-Ts in primary human cells and in a NHP model of B-cell directed CAR-T therapy. Methods: CRISPR/Cas9-mediated PTPN2 deleted (‘KO‘) human CD19 CAR-Ts were assessed for phenotype/function using cytokine secretion and cytotoxicity assays. PTPN2 KO NHP CD20 CAR-Ts were administered to lymphodepleted NHPs using our established model and a dose escalation with Level 1: 6x10 4, Level 2: 6x10 5, Level 3: 3x10 6, and Level 4: 6x10 6 CAR-T/kg, followed by assessment for CAR-T expansion, B cell aplasia, CRS and ICANS. Results: PTPN2 KO was successfully achieved in human CAR-Ts (83.8 + 5.2% deletion). IFNγ production was significantly higher in PTPN2 KO CD19 CAR-Ts vs control cells (35.1 + 0.97% vs 23.4 + 0.98%, p=0.001). In cytotoxicity assays targeting the B-ALL cell line NALM6, PTPN2 KO CD19 CAR-Ts demonstrated significantly increased killing vs control cells (for example, at E:T ratio 1:1 59.6 + 9.8% vs 42.5 + 12.9% p = 0.03). We evaluated the proliferation, efficacy, and toxicity of PTPN2 KO CD20 CAR-Ts in 5 NHPs. The CAR-T PTPN2 KO rate ranged from 63-91%. During dose escalation, no expansion of CAR-Ts was observed at dose levels 1 and 2 (n=1 for each, Fig 1). However, all animals infused at dose level 3 (n=3, 3x10 6 CAR-Ts/kg) demonstrated CAR-T expansion (max expansion 18.6 + 6.8% CAR-Ts) and B cell aplasia, and all animals developed laboratory and clinical signs of CRS and ICANS ( Fig 1). One animal at dose level 3 experienced CRS on day +4 that was severe enough to require tocilizumab, with symptoms subsequently improving. On day +6, this animal also developed ICANS, including ataxia and muscle weakness, requiring 1 dose of Dexamethasone (1mg/kg), after which symptoms resolved. One animal received dose level 4 (6x10 6 CAR-Ts/kg). This recipient displayed earlier and higher expansion of CAR-Ts (day 3: 16.7%, day 7: 56.3% CAR-Ts, Fig.1), and developed severe CRS (with elevated CRP, LDH (not shown) and Ferritin, Fig.1) and ICANS that were unresponsive to treatment with 2 doses of tocilizumab and multiple doses of dexamethasone, with this recipient meeting humane euthanasia endpoints. Importantly, previous animals (n=5) receiving 6-12 x 10 6PTPN2 expressing (WT) CAR-Ts/kg, did not develop severe CRS nor ICANS (and did not require Toci or Dex). This suggests that PTPN2 KO CAR-Ts are associated with augmented toxicities. An extensive terminal analysis of the Dose Level 4 animal was performed; pathology demonstrated widespread cerebral edema and CAR-T CNS infiltration. Because the CAR-T infusion contained both PTPN2 KO and PTPN2 WT CAR-Ts, an assessment could be made for enrichment of PTPN2 KO CAR-Ts in the blood and brain parenchyma. Compared to the infused product (63% KO CAR-Ts, Fig.2), there was enrichment for KO CAR-Ts in the blood (72% KO CAR-Ts) and the brain parenchyma (84% KO CAR-Ts, Fig 2). This suggests increased expansion and CNS infiltration of PTPN2 KO versus PTPN2 WT CAR-Ts. Flow cytometry analysis of the PTPN2 KO CAR-Ts from the blood at maximum expansion revealed high expression of the proliferation and activation markers Ki67 and GZMB (84.6%, 74.5% of all CAR-Ts). Of note, at Dose Level 3, neither CAR-T persistence (15 + 2 days vs 20 + 5 days) nor duration of B cell aplasia (41+ 5 days vs 37 + 3 days) were increased with PTPN2 KO CAR-Ts vs historic controls infused with PTPN2 WT CAR-Ts. Conclusion: We demonstrate that PTPN2 KO CAR-T cells possess increased effector function, proliferation, and CNS infiltration versus PTPN2 WT CAR-Ts. However, this enhanced efficacy was associated with increased severity of CRS and ICANS, emphasizing that careful attention to the dose of PTPN2 KO CAR-Ts would be important. These results also highlight the utility of evaluating gene-modified CAR-Ts in clinically relevant animal models, to thoroughly assess their efficacy and toxicity profiles.

Impact of Dexamethasone (Dex) Dose Strength on Outcomes in Newly Diagnosed Multiple Myeloma (NDMM): A Secondary Analysis of SWOG Studies S0777 and S1211

Background: Dex is a key component of induction regimens for NDMM despite common toxicities including insomnia and anxiety. The E4A03 randomized trial (Rajkumar, Lancet Oncol 2010) demonstrated that dex dosed at 40 mg weekly outperformed higher-intensity dex and established this regimen as the standard of care for NDMM. In standard practice as well as clinical trials, however, dex doses are often reduced to 20 mg weekly or lower (if not stopped entirely) among older patients or among patients experiencing toxicities. As a first step toward establishing the equipoise of planned dex dose reductions in NDMM, we investigated outcomes with patients from two previous SWOG trials to understand the impact of dex dose reductions on post-induction outcomes. Methods: This was a secondary analysis of data from two completed NDMM studies, S0777 (comparing VRd vs Rd) and S1211 (comparing Elo-VRd vs VRd). For this secondary analysis, we analyzed the subset of patients who completed all eight 3-week cycles of induction (or six 4-week cycles in the S0777 Rd arm). As shown in Figure 1A, we defined DEX fullDose as patients for whom the starting dex dose (either 40 mg once per week or 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles) did not change during induction. In contrast, DEX lowered was defined as patients for whom the end-of-induction dex dose and/or frequency were lower than their starting values. As an exploratory analysis, we also compared PFS and OS between the DEX fullDose (no changes to dex strength during induction) and DEX veryLow (dex dosing reduced ≥50% during induction) subgroups. All analyses were landmarked from the end of induction, defined as 24 weeks from registration, to account for the time-dependent nature of dex treatment received. Survival curves were based on the Kaplan-Meier method and comparisons were made using the log-rank test. Results: Of 541 evaluable patients ( n = 441 from S0777, n = 100 from S1211), dex was reduced during induction in 76% ( n = 410). Compared to DEX fullDose patients, DEX lowered patients were more likely to be anemic (37% vs 26%, p = 0.02) but had similar distributions of age ≥70 (24% of DEX lowered vs 26% of DEX fullDose), Performance Status &amp;gt; 1 (15% vs 12%), ISS stage 3 disease (33% vs 27%), ≥ 60% bone marrow plasma cell burden (37% vs 31%), M-spike &amp;gt; 3 g/dL (48% vs 48%) platelets &amp;lt; 150,000 cells/mm 3 (18% vs 14%), baseline LDH ≥ 190 U/L (36% vs 41%), and baseline CRP ≥ 8 mg/L (27% vs 30%). PFS (Figure 1B) was comparable between DEX lowered (median 36 months, 95% CI 29 to 39 months) and DEX fullDose (median 33 months, 95% CI 24 to 48 months) with p = 0.90. Similarly, OS (Figure 1C) was comparable between DEX lowered [median 77 months, 95% CI 68 months to not reached (NR)] and DEX fullDose (median 92 months, 95% CI 65 months to NR) with p = 0.93. In the DEX veryLow subgroup with ≥50% reduction in dex dosing during induction, median PFS was 39 months (95% CI 34 to 50 months) and median OS was NR (95% CI NR to NR). As shown in Figure 1D and Figure 1E, PFS and OS were comparable between these patients and DEX fullDose patients. Discussion: To our knowledge, this is the first analysis of dex dosing strength in NDMM since E4A03. In two separate randomized trials, over half of patients required dex reductions below a starting dose of ~40 mg weekly. Dex dose reductions during induction had no impact on post-induction PFS and OS, even in the subset of patients who required significant dose reductions. Limitations of our post hoc analysis include heterogeneity between dex dosing schedules and lack of cytogenetic data for all patients. We could not discern specifically why dex was lowered, and it is possible that dex might have been lowered disproportionately commonly in patients who had achieved early responses and thus independently did better. Regardless, these results strongly suggest that maintaining dex 40 mg weekly for the entirety of NDMM induction may be unnecessary in the modern era. Cooperative efforts to study a planned dex de-escalation protocol (i.e., once no longer needed for symptom management or as a pre-medication) alongside patient-reported outcome assessments of symptom burden are being planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180820; and in part by Millennium Pharmaceuticals, Inc. (now part of Takeda Pharmaceutical Company), and by Celgene.

Different Epidemiology and Characteristics of Invasive Pulmonary Aspergillosis in Acute Lymphoid Leukemia in Comparison with AML: Results of a Prospective Multicentric Observational Study of the Rete Ematologica Lombarda (REL)

Introduction. Invasive pulmonary aspergillosis (IPA) still affects the outcome of acute leukemia (AL) patients (pts). Although this aspect is better defined in acute myeloid leukemia (AML) ( Candoni et al, Mycoses 2020), some reports show a dismal impact also in acute lymphoid leukemia (ALL) ( Cattaneo et al, Leuk Lymphoma 2019). However, data concerning the epidemiology of IPA in adult ALL patients, as well as the best antifungal prophylaxis strategy, are still lacking. Therefore, to describe the incidence of IPA in AL pts and their clinical characteristics, as well as the predisposing factors, we carried out a prospective multicentric observational study within the Rete Ematologica Lombarda (REL). Methods. All consecutive AL patients diagnosed during a 3-year period and treated with curative intent were recorded. Diagnosis of IPA was defined according to EORTC/MSG criteria ( Donnelly et al, Clin Infect Dis 2020). Data concerning age, gender, AL type, chemotherapy (cht) received, complete remission (CR) achievement, antifungal prophylaxis, duration of neutropenia and 30-day mortality were collected. Patient's characteristics were analysed by standard descriptive statistics. The Student's t-test was used to compare continuous values; the Fisher's exact test was used to compare differences in percentage. P values below 0.05 were considered statistically significant. Results. Between 2018 and 2020, 207 AL pts (AML: 165, ALL: 42) were evaluated in five Hospitals participating to the REL. Median age of the whole cohort was 58y, and M/F ratio 112/95. After induction treatment, CR was achieved in 153 of the 200 evaluable pts (76.5%), more frequently in ALL (38/42, 90.5%) than in AML pts (115/158, 72.8%) (p=0.0146). During induction cht, proven/probable (p/p) and possible (poss) IPA were diagnosed in 32/207 pts (15.4%), equally divided in p/p and poss (16 each, 7.7%). P/p IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs AML: 9/165, 5.4%; p= 0.0235); similarly, considering also poss IPA, incidence was higher, even if not significantly (9/42, 21.4% vs 23/165, 13.9%; p=0.2374). Among ALL pts, IPA was more frequent in pts not achieving CR (2/4, 50%) than CR pts (7/38, 18%), whereas in AML CR achievement did not influence IPA frequency (CR group: 15/115, 13%; no CR group: 7/43: 16.5%). ALL pts were uniformly treated with pediatric-like protocols; in AML pts no statistically significant differences in IPA incidence were observed according to cht received (3+7/like: 13/81, 16%; 3+7+midostaurin: 2/27, 7.4%; FLAG-Ida: 3/21, 14.3%; CPX-351: 4/19, 21%). Antimould prophylaxis was protective against IPA in 202 evaluable pts (Yes: 22/171, 12.9%; No: 10/31, 32.3%, p=0.0134). Among ALL pts only 1 out of 15 (6.7%) receiving antimould prophylaxis developed IPA, as compared to 8/27 (29.6%) of those not receiving antimould prophylaxis (p=0.1235). All but two AML pts developing IPA were on posaconazole prophylaxis. Both mean age and duration of neutropenia were significantly lower in ALL than in AML pts (46.02y vs 57.75y, p&amp;lt;0.0001 and 16.66d vs27.96d, p&amp;lt;0.0001); however, an impact of mean duration of neutropenia on IPA incidence was observed only in ALL pts (IPA group: 24.38d; no IPA group: 14.79d, p=0.0359). Only 2 AML pts died at 30d: 1 (3.1%) out of 32 pts with IPA and 1 (0.6%) out of 175 pts without. No early death was observed in ALL pts. Table 1 summarizes the clinical characteristics of AL pts in relation to IPA. Conclusions. Despite younger age, shorter duration of neutropenia and higher percentage of CR achievement, IPA, particularly p/p, was more frequently observed in ALL pts than AML during induction cht. High dose induction cht seems to have no impact in IPA incidence in AML pts. On the other hand, intensive cht ALL protocols, including high doses of dexamethasone, could have a role in IPA development, as well as the lack of antimould prophylaxis, which is confirmed as a predictive factor for IPA. Therefore, studies with antimould agents as prophylaxis against aspergillosis in ALL pts during inductions would be desirable.

Effect of Preoperative Corticosteroids on Postoperative Glucose Control in Total Joint Arthroplasty

BackgroundDexamethasone is a commonly used perioperative medication for the management of postoperative nausea and vomiting following total joint arthroplasty (TJA). However, concerns have been raised about its potential to cause hyperglycemia. This study aimed to investigate the impact of dexamethasone administration on glucose levels and complications in both diabetic and nondiabetic patients undergoing TJA. MethodsWe performed a retrospective review of 1928 patients who underwent primary total knee and hip arthroplasty procedures at a large tertiary medical institution. Patients were divided into 2 groups based on whether they received preoperative dexamethasone. Postoperative blood glucose values and variability were measured, and data on complications were collected. We performed statistical analysis using descriptive analysis, multivariate logistic regression models, negative binomial regression, and a subset analysis to assess the impact of dexamethasone dose on postoperative glycemic control. ResultsPreoperative dexamethasone did not significantly increase the mean glucose, fasting glucose, glucose variability, or 90-day complications in both the diabetic and nondiabetic groups. Nondiabetic patients who received dexamethasone had a significantly lower rate of intensive care unit admission (P < .01). Additionally, patients who received dexamethasone had a significantly shorter length of hospital stay compared to those who did not (P < .001). ConclusionsPreoperative dexamethasone administration is a safe and effective method for preventing postoperative nausea and vomiting in patients undergoing TJA without significant adverse effects on glucose levels, glucose variability, or infection rates in both diabetics and nondiabetics. Preoperative dexamethasone decreases postoperative length of stay.

QLTI-07. DOSE-EFFECT RELATIONSHIP OF DEXAMETHASONE ON OUTCOMES OF BRAIN METASTASES

Abstract BACKGROUND Dexamethasone is commonly used to manage peritumoral edema and alleviate neurologic symptoms in patients with intracranial tumors. The optimal dexamethasone dose for brain metastases is unknown and widely variable. Recent literature reports the most common regimen is 4 mg four times daily. However, the half-life of dexamethasone is 35-54 hours, suggesting that such frequent dosing may be unnecessary. We explored the dose-effect relationship of dexamethasone on brain metastases patient outcomes to improve quality of care. METHODS We retrospectively identified 100 patients (1/1/2016 – 12/31/2022) with brain metastases who were treated with dexamethasone and had adequate follow-up. All patients received standard oncologic care including chemotherapy, radiotherapy, and/or surgical intervention. We evaluated the association between dexamethasone dosing regimens (&amp;lt; 4 mg twice daily versus &amp;gt; 4 mg three times daily), clinical outcomes (performance status, clinical and radiographic response to corticosteroids, survival), and dexamethasone adverse effects during the acute presentation and at first neuro-oncologic follow-up. RESULTS Seventy-two patients received less frequent dexamethasone dosing (&amp;lt; 4 mg twice daily), while 28 received more frequent dexamethasone dosing (&amp;gt; 4 mg three times daily). Patients with higher frequency dexamethasone dosing were more likely to have radiographic evidence of midline shift (p &amp;lt; 0.001), compression of ventricles (p &amp;lt; 0.001), and herniation (p = 0.0020) at presentation. Those with more frequent dosing more often demonstrated radiographic response to dexamethasone (67.9% vs. 45.8%, p = 0.0323), but there were no differences in symptomatic improvement, Karnofsky Performance Status, seizure reduction, survival, or the frequency of adverse events (e.g., hyperglycemia, hypertension, infection, psychosis) between the two cohorts. CONCLUSIONS These results suggest that for most patients with brain metastases, less frequent dexamethasone dosing may lead to clinical outcomes that are similar to those patients who received more frequent dosing. However, higher doses of dexamethasone can be considered for those with more concerning radiologic features.