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Haematologica Feb 2024Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need,... (Clinical Trial)
Clinical Trial
Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD-) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD- complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Recurrence
PubMed: 37584290
DOI: 10.3324/haematol.2023.283073 -
Microbiome Nov 2023Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with...
BACKGROUND
Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Gut microbial dysbiosis is associated with neurological diseases; however, the mechanisms by which the microbiota regulates postoperative gastrointestinal and cognitive function are incompletely understood.
METHODS
Behavioral testing, MiSeq 16S rRNA gene sequencing, non-target metabolism, intestinal permeability detection, protein assays, and immunofluorescence staining were employed to discern the impacts of surgery on microbial profiles, intestinal barriers, serum metabolism, and the brain. Interventions in mice included fecal microbiota transplantation, the anti-inflammatory agent dexamethasone, Lactobacillus supplementation, indole propionic acid supplementation, and palmitic amide administration.
RESULTS
Surgery-induced cognitive impairment occurs predominantly in aged mice, and surgery-induced alterations in the microbiota composition profile exacerbate intestinal barrier disruption in aged mice. These adverse effects can be mitigated by transferring microbiota from young donors or by bolstering the intestinal barrier function using dexamethasone, Lactobacillus, or indole propionic acid. Moreover, microbiota composition profiles can be restored by transplanting feces from young mice to aged surgical mice, improving neuropathology and cognitive function, and these effects coincide with increased intestinal permeability. Metabolomic screening identified alterations in metabolites in mouse serum after surgery, especially the increase in palmitic amide. Palmitic amide levels in serum and brain can be decreased by transplanting feces from young mice to aged surgical mice. Oral palmitic amide exacerbates cognitive impairment and neuropathological changes in mice.
CONCLUSIONS
Gut microbial dysbiosis in mice after surgery is a key mechanism leading to cognition dysfunction, which disrupts the intestinal barrier and metabolic abnormalities, resulting in neuroinflammation and dendritic spine loss. Intestinal barrier damage and high level of palmitic amide in old mice may be the cause of high incidence of PND in the elderly. Preoperative microbiota regulation and intestinal barrier restoration may be of therapeutic benefit in preventing PND. Video Abstract.
Topics: Animals; Mice; Cognitive Dysfunction; Dexamethasone; Dysbiosis; Gastrointestinal Microbiome; Indoles; Mice, Inbred C57BL; RNA, Ribosomal, 16S
PubMed: 37936242
DOI: 10.1186/s40168-023-01689-6 -
Journal of Perinatal Medicine Nov 2023Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects. (Review)
Review
BACKGROUND
Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects.
CONTENT
A systematic review was performed to determine the childhood and adolescent cardiopulmonary and cognitive effects of dexamethasone systemically administered to preterm infants during neonatal intensive care. Relevant studies were identified by searching two electronic health databases and the grey literature. Spirometry assessments were used as respiratory outcomes, blood pressure and echocardiography assessments as cardiovascular outcomes and cognitive and motor function as cognitive outcomes. From 1,479 articles initially identified, 18 studies (overall 1,609 patients) were included (respiratory n=8, cardiovascular n=2, cognitive n=10); all were observational cohort studies. Dexamethasone exposure was associated with worse pulmonary outcomes in children and adolescents (more abnormal FVC and FEV1:FVC z scores). Dexamethasone exposure was associated in one study with lower IQ scores compared to preterm controls (mean 78.2 [SD 15.0] vs. 84.4 [12.6], [p=0.008]) and in two others was associated with lower total and performance IQ when compared to term controls (p<0.001).
SUMMARY AND OUTLOOK
Postnatal dexamethasone exposure has a negative influence on pulmonary and cognitive outcomes in childhood and adolescence. Medications with a better benefit to risk profile need to be identified.
Topics: Adolescent; Child; Humans; Infant; Infant, Newborn; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Bronchopulmonary Dysplasia; Chronic Disease; Dexamethasone; Glucocorticoids; Infant, Premature
PubMed: 37606507
DOI: 10.1515/jpm-2023-0297 -
Annals of Hematology Sep 2023This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and...
This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.
Topics: Humans; Lenalidomide; Multiple Myeloma; Dexamethasone; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37341778
DOI: 10.1007/s00277-023-05212-7 -
European Archives of... Aug 2023COVID-19 can result in an extensive range of extrapulmonary, and neurological signs and symptoms such as olfactory and/or taste dysfunction, and otologic symptoms. The... (Review)
Review
INTRODUCTION
COVID-19 can result in an extensive range of extrapulmonary, and neurological signs and symptoms such as olfactory and/or taste dysfunction, and otologic symptoms. The aim of this study was to investigate the hearing loss manifestation from COVID-19.
METHODS
The goal of this umbrella review was to examine hearing loss associated with COVID-19 disease. English literature published until October 15, 2022 in online databases including PubMed, Scopus, Web of Science, and Embase was considered for this purpose. Eligibility of the articles for subsequent data extraction was evaluated in a two-step selection process with consideration to an inclusion/exclusion criterion. This review followed the PRISMA protocol and the Amstar-2 checklist for quality assessment.
RESULTS
A total of four treatment strategies were used by different studies which included oral corticosteroids, intratympanic corticosteroids, combined oral and intratympanic corticosteroids, and hyperbaric oxygen therapy. Five studies investigated corticosteroid use in the forms of oral or intratympanic injection; four studies reported (complete or partial) hearing improvements after steroid treatment, while one study stated no significant improvement in hearing function. One study reported that oral corticosteroid monotherapy alone was not effective, while vestibular symptoms were ameliorated by a combination of oral prednisone, intratympanic dexamethasone injection, and hydroxychloroquine.
CONCLUSION
The findings suggest that despite being one of the rare complications of COVID-19, hearing loss can impact a patient's quality of life. The most common type reported was sensorineural hearing loss, which can be diagnosed with variable techniques.
Topics: Humans; Hearing Loss, Sudden; Quality of Life; COVID-19; Hearing Loss, Sensorineural; Adrenal Cortex Hormones; Deafness; Injection, Intratympanic; Treatment Outcome; Dexamethasone; Glucocorticoids
PubMed: 37093291
DOI: 10.1007/s00405-023-07982-2 -
Blood Advances Dec 2023
Topics: Humans; Multiple Myeloma; Bortezomib; Thalidomide; Renal Insufficiency; Dexamethasone
PubMed: 37922425
DOI: 10.1182/bloodadvances.2023011428 -
Proceedings of the National Academy of... Aug 2023Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or...
Glucocorticoids (GC) are potent anti-inflammatory agents, broadly used to treat acute and chronic inflammatory diseases, e.g., critically ill COVID-19 patients or patients with chronic inflammatory bowel diseases. GC not only limit inflammation but also promote its resolution although the underlying mechanisms are obscure. Here, we reveal reciprocal regulation of 15-lipoxygenase (LOX) isoform expression in human monocyte/macrophage lineages by GC with respective consequences for the biosynthesis of specialized proresolving mediators (SPM) and their 15-LOX-derived monohydroxylated precursors (mono-15-OH). Dexamethasone robustly up-regulated pre-mRNA, mRNA, and protein levels of ALOX15B/15-LOX-2 in blood monocyte-derived macrophage (MDM) phenotypes, causing elevated SPM and mono-15-OH production in inflammatory cell types. In sharp contrast, dexamethasone blocked ALOX15/15-LOX-1 expression and impaired SPM formation in proresolving M2-MDM. These dexamethasone actions were mimicked by prednisolone and hydrocortisone but not by progesterone, and they were counteracted by the GC receptor (GR) antagonist RU486. Chromatin immunoprecipitation (ChIP) assays revealed robust GR recruitment to a putative enhancer region within intron 3 of the ALOX15B gene but not to the transcription start site. Knockdown of 15-LOX-2 in M1-MDM abolished GC-induced SPM formation and mono-15-OH production. Finally, ALOX15B/15-LOX-2 upregulation was evident in human monocytes from patients with GC-treated COVID-19 or patients with IBD. Our findings may explain the proresolving GC actions and offer opportunities for optimizing GC pharmacotherapy and proresolving mediator production.
Topics: Humans; Glucocorticoids; Arachidonate 15-Lipoxygenase; COVID-19; Inflammation; Dexamethasone; Lipids
PubMed: 37603745
DOI: 10.1073/pnas.2302070120 -
Journal of Thrombosis and Haemostasis :... Nov 2023Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune...
BACKGROUND
Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune thrombocytopenia. However, their efficacy and mechanisms of action in immune thrombocytopenia are not fully understood.
OBJECTIVES
To investigate the mechanism of glucocorticoid actions on platelet production.
METHODS
The actions of glucocorticoids on platelet production were studied combining in vivo, ex vivo and in vitro approaches.
RESULTS
Dexamethasone reduced bleeding in mice and rapidly increased circulating young platelet counts. In vitro glucocorticoid treatment stimulated proplatelet formation by megakaryocytes and platelet-like particle release. This effect was blocked by glucocorticoid receptor antagonist RU486, indicating a glucocorticoid receptor-dependent mechanism. Genome-wide analysis revealed that dexamethasone regulates the expression of >1000 genes related to numerous cellular functions, including predominant cytoplasm and cytoskeleton reorganization. Dexamethasone and other glucocorticoids induced the expression of Gda (the gene encoding guanine deaminase), which has been reported to have a role in dendrite development. Inhibition of guanine deaminase enzymatic activity blocked dexamethasone stimulation of proplatelet formation, implicating a critical role for this enzyme in glucocorticoid-mediated platelet production.
CONCLUSION
Our findings identify glucocorticoids as new regulators of thrombopoiesis.
Topics: Mice; Animals; Megakaryocytes; Thrombopoiesis; Glucocorticoids; Purpura, Thrombocytopenic, Idiopathic; Receptors, Glucocorticoid; Guanine Deaminase; Transcriptome; Blood Platelets; Thrombocytopenia; Dexamethasone
PubMed: 37336437
DOI: 10.1016/j.jtha.2023.06.012 -
Frontiers in Immunology 2023Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the...
BACKGROUND
Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.
OBJECTIVE
We combined functional immunological assays and an omics-based approach to investigate the and effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.
METHODS
Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.
RESULTS
Dexamethasone efficiently inhibited SARS-CoV-2-induced expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.
CONCLUSION
We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.
Topics: Humans; Cytokines; Leukocytes, Mononuclear; Ligands; Proteomics; COVID-19; SARS-CoV-2; COVID-19 Drug Treatment; Interferon Type I; Tumor Necrosis Factor-alpha; Dexamethasone
PubMed: 37614228
DOI: 10.3389/fimmu.2023.1233318