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Lancet (London, England) May 2024Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger)... (Randomized Controlled Trial)
Randomized Controlled Trial
Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of...
BACKGROUND
Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT.
METHODS
The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m on day 0 or 1, intravenous cyclophosphamide 750 mg/m on day 1, intravenous doxorubicin 50 mg/m on day 1, intravenous vincristine 1·4 mg/m on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258.
FINDINGS
Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238).
INTERPRETATION
Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined.
FUNDING
Janssen and Leukemia & Lymphoma Society.
Topics: Humans; Lymphoma, Mantle-Cell; Adenine; Piperidines; Middle Aged; Male; Antineoplastic Combined Chemotherapy Protocols; Female; Transplantation, Autologous; Vincristine; Rituximab; Adult; Cyclophosphamide; Aged; Europe; Hematopoietic Stem Cell Transplantation; Prednisone; Doxorubicin; Young Adult; Dexamethasone; Adolescent; Israel; Treatment Outcome
PubMed: 38705160
DOI: 10.1016/S0140-6736(24)00184-3 -
BMC Anesthesiology Mar 2024Postoperative nausea and vomiting (PONV) is one of the most common adverse events following orthognathic surgery. It's a distressing feeling for patients and continues... (Review)
Review
INTRODUCTION
Postoperative nausea and vomiting (PONV) is one of the most common adverse events following orthognathic surgery. It's a distressing feeling for patients and continues to be the cause of postoperative complications such as bleeding, delayed healing, and wound infection. This scoping review aims to identify effective PONV prophylaxis strategies during orthognathic surgery that have emerged in the past 15 years.
METHODS
We searched Pubmed, Cochrane Controlled Register of Trials, and Embase from 2008 to May 2023. Studies meeting the following criteria were eligible for inclusion: (1) recruited patients undergo any orthognathic surgery; (2) evaluated any pharmacologic or non-pharmacologic method to prevent PONV. Studies meeting the following criteria were excluded: (1) case series, review papers, or retrospective studies; (2) did not report our prespecified outcomes.
RESULTS
Twenty-one studies were included in this review. Pharmacological methods for PONV prevention include ondansetron and dexamethasone (3 studies), peripheral nerve block technique (4 studies), dexmedetomidine (1 study), pregabalin (2 studies), nefopam (2 studies), remifentanil (1 study), propofol (2 studies), and penehyclidine (1 study). Non-pharmacologic methods include capsicum plaster (1 study), throat packs (2 studies) and gastric aspiration (2 studies).
CONCLUSIONS
Based on current evidence, we conclude that prophylactic antiemetics like dexamethasone, ondansetron, and penehyclidine are the first defense against PONV. Multimodal analgesia with nerve block techniques and non-opioid analgesics should be considered due to their notable opioid-sparing and PONV preventive effect. For the non-pharmacological methods, throat packs are not recommended for routine use because of their poor effect and serious complications. More prospective RCTs are required to confirm whether gastric aspiration can prevent PONV effectively for patients undergoing orthognathic surgery.
Topics: Humans; Postoperative Nausea and Vomiting; Ondansetron; Orthognathic Surgery; Prospective Studies; Retrospective Studies; Antiemetics; Dexamethasone
PubMed: 38539078
DOI: 10.1186/s12871-024-02510-z -
Acta Biomaterialia Dec 2023In cases of blinding disease or trauma, hydrogels have been proposed as scaffolds for corneal regeneration and vehicles for ocular drug delivery. Restoration of corneal...
In cases of blinding disease or trauma, hydrogels have been proposed as scaffolds for corneal regeneration and vehicles for ocular drug delivery. Restoration of corneal transparency, augmenting a thin cornea and postoperative drug delivery are particularly challenging in resource-limited regions where drug availability and patient compliance may be suboptimal. Here, we report a bioengineered hydrogel based on porcine skin collagen as an alternative to human donor corneal tissue for applications where long-term stability of the hydrogel is required. The hydrogel is reinforced with cellulose nanofibers extracted from the Ciona intestinalis sea invertebrate followed by double chemical and photochemical crosslinking. The hydrogel is additionally loaded with dexamethasone to provide sustained anti-inflammatory activity. The reinforced double-crosslinked hydrogel after drug loading maintained high optical transparency with significantly improved mechanical characteristics compared to non-reinforced hydrogels, while supporting a gradual sustained drug release for 60 days in vitro. Dexamethasone, after exposure to crosslinking and sterilization procedures used in hydrogel production, inhibited tube formation and cell migration of TNFα-stimulated vascular endothelial cells. The drug-loaded hydrogels suppressed key pro-inflammatory cytokines CCL2 and CXCL5 in TNFα-stimulated human corneal epithelial cells. Eight weeks after intra-stromal implantation in the cornea of 12 New-Zealand white rabbits subjected to an inflammatory suture stimulus, the dexamethasone-releasing hydrogels suppressed TNFα, MMP-9, and leukocyte and fibroblast cell invasion, resulting in reduced corneal haze, sustained corneal thickness and stromal morphology, and reduced overall vessel invasion. This collagen-nanocellulose double-crosslinked hydrogel can be implanted to treat corneal stromal disease while suppressing inflammation and maintaining transparency after corneal transplantation. STATEMENT OF SIGNIFICANCE: To treat blinding diseases, hydrogel scaffolds have been proposed to facilitate corneal restoration and ocular drug delivery. Here, we improve on a clinically tested collagen-based scaffold to improve mechanical robustness and enzymatic resistance by incorporating sustainably sourced nanocellulose and dual chemical-photochemical crosslinking to reinforce the scaffold, while simultaneously achieving sustained release of an incorporated anti-inflammatory drug, dexamethasone. Evaluated in the context of a corneal disease model with inflammation, the drug-releasing nanocellulose-reinforced collagen scaffold maintained the cornea's transparency and resisted degradation while suppressing inflammation postoperatively. This biomaterial could therefore potentially be applied in a wider range of sight-threatening diseases, overcoming suboptimal administration of postoperative medications to maintain hydrogel integrity and good vision.
Topics: Humans; Animals; Rabbits; Tumor Necrosis Factor-alpha; Endothelial Cells; Hydrogels; Cornea; Collagen; Anti-Inflammatory Agents; Inflammation; Dexamethasone
PubMed: 37866722
DOI: 10.1016/j.actbio.2023.10.020 -
Inflammopharmacology Oct 2023The present review critically appraised the randomized clinical trials that compared mortality outcomes between intermediate- to high-dose dexamethasone and low-dose... (Meta-Analysis)
Meta-Analysis
Intermediate- to high-dose dexamethasone versus low-dose dexamethasone in patients with COVID-19 requiring respiratory support: a systematic review and meta-analysis of randomized trials.
The present review critically appraised the randomized clinical trials that compared mortality outcomes between intermediate- to high-dose dexamethasone and low-dose dexamethasonein patients with COVID-19 and reported pooled mortality risk estimates associated with these two dosing regimens of dexamethasone. The systematic searching of electronic databases was limited to randomized clinical trials that compared mortality outcomes between intermediate- to high-dose dexamethasone with low-dose dexamethasone in patients with COVID-19 requiring respiratory support. The primary outcome of interest in this review was all-cause mortality. A total of eight trials with 1800 patients randomized to receive intermediate to high-dose dexamethasone and 1715 patients randomized to low-dose dexamethasone were included. The meta-analysis of six trials revealed no significant difference in the risk of 28-day all-cause mortality between intermediate- to high-dose dexamethasone and low-dose dexamethasone (odds ratio 1.16, 95% confidence interval, 0.77-1.74). Similarly, the meta-analysis of five trials revealed no significant difference between the two doses regarding 60-day all-cause mortality (odds ratio 0.96, 95% confidence interval 0.74-1.26). The results suggest intermediate- to high-dose dexamethasone to be as effective as low-dose dexamethasone in reducing the risk of mortality among patients with COVID-19 requiring respiratory support. However, higher dexamethasone doses could expose patients with COVID-19 to an increased risk of adverse events, such as hyperglycemia.
Topics: Humans; COVID-19; Dexamethasone; COVID-19 Drug Treatment; Randomized Controlled Trials as Topic
PubMed: 37266814
DOI: 10.1007/s10787-023-01251-8 -
Clinical Lymphoma, Myeloma & Leukemia Mar 2024A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use...
INTRODUCTION
A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment.
METHODS
Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed.
RESULTS
Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without.
CONCLUSION
Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.
Topics: Humans; Multiple Myeloma; Bortezomib; Lenalidomide; Frailty; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 38072743
DOI: 10.1016/j.clml.2023.10.009 -
Journal of Enzyme Inhibition and... Dec 2023Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and...
Design, synthesis, anti-inflammatory evaluation, and molecular modelling of new coumarin-based analogs combined curcumin and other heterocycles as potential TNF-α production inhibitors upregulating Nrf2/HO-1, downregulating AKT/mTOR signalling pathways and downregulating NF-κB in LPS induced...
Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound , which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC value of 5.32 μM. The anti-inflammatory effects of were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that and dexamethasone bind to the same TNF-α pocket, suggesting that has potential as a therapeutic agent superior to dexamethasone for TNF-α.
Topics: Humans; Anti-Inflammatory Agents; Coumarins; Curcumin; Cytokines; Dexamethasone; Inflammation; Lipopolysaccharides; Macrophages; NF-E2-Related Factor 2; NF-kappa B; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha
PubMed: 37558232
DOI: 10.1080/14756366.2023.2243551 -
Bone Marrow Transplantation Nov 2023In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an...
Carfilzomib, lenalidomide and dexamethasone followed by a second ASCT is an effective strategy in first relapse multiple myeloma: a study on behalf of the Chronic malignancies working party of the EBMT.
In the setting of a first relapse of multiple myeloma (MM), a second autologous stem cell transplant (ASCT) following carfilzomib-lenalidomide-dexamethasone (KRd) is an option, although there is scarce data concerning this approach. We performed a retrospective study involving 22 EBMT-affiliated centers. Eligible MM patients had received a second-line treatment with KRd induction followed by a second ASCT between 2016 and 2018. Primary objective was to estimate progression-free survival (PFS) and overall survival (OS). Secondary objectives were to assess the response rate and identify significant variables affecting PFS and OS. Fifty-one patients were identified, with a median age of 62 years. Median PFS after ASCT was 29.5 months while 24- and 36-months OS rates were 92.1% and 84.5%, respectively. Variables affecting PFS were an interval over four years between transplants and the achievement of a very good partial response (VGPR) or better before the relapse ASCT. Our study suggests that a relapse treatment with ASCT after KRd induction is an effective strategy for patients with a lenalidomide-sensitive first relapse. Patients with at least four years of remission after a frontline ASCT and who achieved at least a VGPR after KRd induction appear to benefit the most from this approach.
Topics: Humans; Middle Aged; Multiple Myeloma; Lenalidomide; Retrospective Studies; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Dexamethasone; Transplantation, Autologous
PubMed: 37543712
DOI: 10.1038/s41409-023-02048-7 -
Nature Communications Apr 2024Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are...
Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.
Topics: Animals; Male; Histone Demethylases; Glucocorticoids; Dexamethasone; Receptors, Glucocorticoid; Mice; Muscular Atrophy; Muscle, Skeletal; Mice, Inbred C57BL; Gene Expression Regulation
PubMed: 38670969
DOI: 10.1038/s41467-024-47846-9 -
ACS Applied Materials & Interfaces Nov 2023Enhancing osteogenesis via modulating immune cells is emerging as a new approach to address the current challenges in repairing bone defects and fractures. However, much...
Enhancing osteogenesis via modulating immune cells is emerging as a new approach to address the current challenges in repairing bone defects and fractures. However, much remains unknown about the crosstalk between immune cells and osteolineage cells during bone formation. Moreover, biomaterial scaffold-based approaches to effectively modulate this crosstalk to favor bone healing are also lacking. This study is the first to investigate the interactions between macrophages and mesenchymal stem cells (MSCs) in co-cultures with the sustained release of an anti-inflammatory and pro-osteogenesis drug (dexamethasone) from three-dimensional (3D)-printed scaffolds. We successfully achieved the sustained release of dexamethasone from polycaprolactone (PCL) by adding the excipient-sucrose acetate isobutyrate (SAIB). Dexamethasone was released over 35 days in the 17-163 nM range. The osteogenic differentiation of MSCs was enhanced by M1 macrophages at early time points. The late-stage mineralization was dominated by dexamethasone, with little contribution from the macrophages. Besides confirming BMP-2 whose secretion was promoted by both dexamethasone and M1 macrophages as a soluble mediator for enhanced osteogenesis, IL-6 was found to be a possible new soluble factor that mediated osteogenesis in macrophage-MSC co-cultures. The phenotype switching from M1 to M2 was drastically enhanced by the scaffold-released dexamethasone but only marginally by the co-cultured MSCs. Our results offer new insight into macrophage-MSC crosstalk and demonstrate the potential of using drug-release scaffolds to both modulate inflammation and enhance bone regeneration.
PubMed: 38016086
DOI: 10.1021/acsami.3c09774 -
PloS One 2024Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in...
OBJECTIVE
Prescription trends and patterns of anti-COVID-19 drugs in hospitalized patients were examined based on real world data to understand the use of anti-COVID-19 drugs in clinical practice in Japan.
DESIGN
The longitudinal and cross-sectional study was conducted utilizing data from January 1, 2019 to December 31, 2021 of the MID-NET® medical information database, which stored the electronic medical records, administrative claim data, and diagnosis procedure combination data of patients in Japan.
PARTICIPANTS
Hospitalized patients with a COVID-19-related diagnosis who received at least one anti-COVID-19 drug between April 1, 2020 and December 31, 2021.
EXPOSURES
The following 14 drugs were included in this study: remdesivir, baricitinib, combination product of casirivimab and imdevimab, favipiravir, dexamethasone, ivermectin, azithromycin, nafamostat mesylate, camostat mesylate, ciclesonide, tocilizumab, sarilumab, combination product of lopinavir and ritonavir, and hydroxychloroquine.
RESULTS
We identified 5,717 patients hospitalized with COVID-19 and prescribed at least one anti-COVID-19 drug. The entire cohort generally included patients over 41-50 years and more males. The most common prescription pattern was dexamethasone monotherapy (22.9%), followed by the concomitant use of remdesivir and dexamethasone (15.0%), azithromycin monotherapy (15.0%), remdesivir monotherapy (10.2%), and nafamostat mesylate monotherapy (8.5%). However, an often prescribed anti-COVID-19 drug differed depending on the period.
CONCLUSIONS AND RELEVANCE
This study revealed the real-world situation of anti-COVID-19 drug prescriptions in hospitalized COVID-19 patients in Japan. A prescribed drug would depend on the latest scientific evidence, such as efficacy, safety, and approval status, at the time of prescription. Understanding the prescription of anti-COVID-19 drugs will be important for providing the most up-to-date treatments to patients and evaluating the benefit and/or risk of anti-COVID-19 drugs based on the utilization of an electronic medical record database.
Topics: Male; Humans; COVID-19; SARS-CoV-2; Azithromycin; Japan; Cross-Sectional Studies; Dexamethasone; Prescriptions; Antiviral Agents; Benzamidines; Guanidines
PubMed: 38277429
DOI: 10.1371/journal.pone.0297679