Glucocorticoid Receptor 

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  • ||||||||||  Darzalex (daratumumab) / J&J, Ninlaro (ixazomib) / Takeda
    Global Treatment Standard in Multiple Myeloma Remains Elusive: Updated Results from the INSIGHT MM Global, Prospective, Observational Study (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2724;    
    P=N/A
    Unlike NDMM pts, RRMM pts were more likely to receive alternative PIs to V in =2nd LOT (IRd 6.8%; KRd 6.7%; VRd 2.7%), & daratumumab (D) was used instead of or alongside PIs in some triplets (DRd 4.9%; VDd 4.5%)...Conclusions V-based triplets were the most common frontline treatment in NDMM pts in all regions. Regimens used in later LOTs in RRMM pts were more varied across regions, & generally included greater use of doublets, PIs other than V, & mAbs such as D. Acknowledging that treatment use is dependent on approval status & availability, this analysis shows that, while global frontline standard of care (SOC) is broadly established, there remains no consistent SOC in later LOTs; adoption of newer therapies, such as mAbs, varies across regions worldwide.
  • ||||||||||  Polivy (polatuzumab vedotin-piiq) / Roche, Monjuvi (tafasitamab-cxix) / MorphoSys, Xencor, Incyte, Specialised Therap, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
    Management of Canadian Patients (Pts) with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) in the Real-World (Hall D (Ernest N. Morial Convention Center)) -  Nov 4, 2022 - Abstract #ASH2022ASH_2512;    
    P=N/A, P2
    Tx patterns in Canadian pts with R/R DLBCL demonstrate that although ASCT is the 2L standard of care (SoC) for eligible pts, there is no SoC in ASCT-ineligible pts or in those who do not receive a transplant. Following 1L tx, different approved therapies were used for 2L and beyond.
  • ||||||||||  Bosulif (bosutinib) / Pfizer, foretinib (GSK1363089) / Exelixis
    Targeting Hyperactivated Lck in PAX5 Rearranged Pediatric B-Cell Precursors Acute Lymphoblastic Leukemia (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2177;    
    As previously showed by us, we demonstrated the efficacy of the LCK-inhibitor Nintedanib, as single agent or in combination with conventional chemotherapy, both ex-vivo and in a patient-derived xenograft model, showing a synergistic effect with dexamethasone...From the drug screening, we selected Dasatinib, Bosutinib and Foretinib, known to be among the top 10 most potent LCK ligands...This study provides new insights in the pathogenic mechanisms of poor risk Ph-like leukemia and identifies a potential novel therapy for targeting the PAX5t group. Moreover, in general this study opens the scenario to target LCK kinase activity in further BCP-ALL subgroups.
  • ||||||||||  dexamethasone / Generic mfg., arsenic trioxide / Generic mfg.
    UBR5 Is a Hect E3 Ubiquitin Ligase That Regulates Chromatin Bound Nuclear Hormone Receptor Stability (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2102;    
    ChIP and RNA-seq in A549 cells following dexamethasone treatment revealed that UBR5 also co-localizes with GR and regulates its transcription, suggesting UBR5-mediated degradation may be a general regulator of multiple NRs and their transcriptional activities. Our findings reveal a novel molecular mechanism regulating nuclear hormone receptors: ligand dependent E3 ligase binding on chromatin, leading to degradation and transcriptional regulation.
  • ||||||||||  Plasma Exchange for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitor Therapy: Implications for Clinical Care and Clinical Trial Design (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_2032;    
    ICI constructs were IgG1 anti-PD-L1 (envafolimab, durvalumab) and IgG4 anti-PD-1 (nivolumab, cemiplimab)...Grade 4 bleeding occurred in the patient receiving enoxaparin and DAPT and led to discontinuation of TPE after 2 sessions. Our experience supports the following when considering TPE for irAEs: 1) exclusion of patients with high bleeding risk, or use of 100% FFP replacement and every other day TPE; 2) meticulous non-biomarker irAE assessment during and after TPE; 3) RCT design includes irAE relapse timing and rates and long term follow-up to assess cumulative immunosuppression and tumor outcome; 4) serial drug levels and correlative studies (e.g. cytokines, autoantibodies) to better understand TPE mechanisms, persistence of irAEs, and long term ICI anti-tumor benefit.
  • ||||||||||  flonoltinib / Baoling Bio
    Flonoltinib, a Novel JAK2/FLT3 Inhibitor, Potently Treats Hemophagocytic Lymphohistiocytosis and Increases Sensitivity to Dexamethasone (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_1920;    
    Subsequently, secondary HLH murine model was established by intraperitoneal injection of 50 µg CpG-ODN1826 to C57BL/6 mice...Flonoltinib plus dexamethasone also exerted stronger effect in reducing spleen weight and elevating CBC than etoposide plus dexamethasone...Conclusions Compared to ruxolitinib, the novel JAK2/FLT3 inhibitor, flonoltinib, was more effective in treating HLH. Flonoltinib was synergistic with dexamethasone by restoring GCR nuclear transport, which increased sensitivity to dexamethasone.
  • ||||||||||  etoposide IV / Generic mfg.
    Early Response Parameters during Etoposide-Based Hemophagocytic Lymphohistiocytosis Treatment in Children Predict Early Mortality (ENMCC - Hall D) -  Nov 4, 2022 - Abstract #ASH2022ASH_1913;    
    Conclusions Five early prognostic laboratory indicators were identified in pediatric patients receiving etoposide-based therapy for HLH, these include not only some HLH-94 diagnostic criteria but also other laboratory parameters. Survival analysis identified that the presence of three or more unfavorable day 7 prognostic indicators is associated with significantly high risk of pre-BMT mortality and may indicate the need for early escalation of therapy.
  • ||||||||||  epcoritamab (GEN-3013) / Genmab, AbbVie
    Subcutaneous Epcoritamab in Patients with Richter's Syndrome: Early Results from Phase 1b/2 Trial (EPCORE CLL-1) (ENMCC - R06-R09) -  Nov 4, 2022 - Abstract #ASH2022ASH_1772;    
    P1b/2
    This safety profile was consistent with previous reports of epcoritamab monotherapy, and no new safety signals were reported. Preliminary efficacy findings show that SC epcoritamab has encouraging single-agent activity in RS-LBCL, with high overall and complete response rates observed and the majority of responses seen at the first (wk 6) assessment.
  • ||||||||||  Integrated High-Throughput Drug Profiling and CRISPR Screening Identify Novel Pathway Vulnerabilities of Leukemic Stem Cells in Chronic Myeloid Leukemia (ENMCC - 275-277) -  Nov 4, 2022 - Abstract #ASH2022ASH_1749;    
    Combination of imatinib with idasanutlin, venetoclax, AZD1775 and dexamethasone led to synergistic inhibition of CML-LSCs...We identified specific sensitivity of CML CD34+CD38- cells to mepacrine, RG7112, idasanutlin, and navitoclax...Imatinib, dasatinib, and tivozanib showed a similar profile of resistance and sensitizing genes, while AZD1775 and mepacrine had unique profiles...Furthermore, combination of TKI with deubiquitinase inhibitors induced enhanced TKI sensitivity in KCTD5-KO cells. In conclusion, we discovered novel mechanisms of primary TKI-resistance and drug vulnerabilities of CML-LSCs, which potentially enable eradication of LSCs in CML patients and hence pave the way for the achievement of functional cure in CML patients.
  • ||||||||||  Empliciti (elotuzumab) / AbbVie, BMS
    Single-Cell RNA-Sequencing Identifies Immune Biomarkers of Progression in Patients with High-Risk Smoldering Multiple Myeloma Treated with Immunotherapy (ENMCC - R02-R05) -  Nov 4, 2022 - Abstract #ASH2022ASH_1423;    
    Discussion Collectively, our results indicate that the similarity of a patient’s BM immune cell composition to that of healthy donors can be harnessed for prognostication both at diagnosis and post-therapy, which could have implications in risk stratification at diagnosis, trial design and monitoring of response to therapy. Moreover, PB-based immune profiling may have diagnostic and prognostic utility, potentially enabling regular assessments of immune dysregulation in patients.
  • ||||||||||  Nplate (romiplostim) / Amgen, Kyowa Kirin, Promacta (eltrombopag) / Novartis, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
    Do Children with Immune Thrombocytopenia Have Cerebral Microbleeds? (ENMCC - 275-277) -  Nov 4, 2022 - Abstract #ASH2022ASH_1308;    
    Of the cohort, 73% had received treatment including: tranexamic acid, steroids, thrombopoietin-receptor agonists-TPO-RA, intravenous immunoglobulins (IVIg), rituximab and others, with a median treatment episodes of 3 and 68% are currently on TPO-RA treatment...He had multi-refractory disease, 3002 days with a platelet count under 10 x 109/L, a paediatric bleeding score of 14 and minimal responses to IVIg, prednisone, dexamethasone, rituximab, eltrombopag, romiplostim, sirolimus and mycophenolate mofetil...In this study, CMBs were not associated with poor HRQoL, fatigue or cognitive impairment. A national study with differing centres is required to better understand the significance of this novel finding of CMBs in childhood ITP.
  • ||||||||||  methylprednisolone sodium succinate / Generic mfg.
    Journal:  Double-Blind Randomized Controlled Trial Comparing Platelet-Rich Plasma With Intra-Articular Corticosteroid Injections in Patients With Bilateral Knee Osteoarthritis. (Pubmed Central) -  Nov 4, 2022   
    They were randomized to receive an intra-articular PRP injection into one knee and a methylprednisolone injection with a local anesthetic into the contralateral knee...The secondary outcome also delivered the same result with improvement at all time points but no statistically significant difference (F=0.168, p=0.85). Conclusions Both corticosteroids and PRP interventions are effective in improving pain, stiffness, and function in patients with bilateral knee osteoarthritis up to six months with no statistically significant difference between the two.
  • ||||||||||  prednisolone / Generic mfg.
    Journal, Video:  Bilateral cholesterol granulomas in the middle ear cavities of a cat with sinonasal disease successfully removed via video-otoscopy. (Pubmed Central) -  Nov 4, 2022   
    Conclusions Both corticosteroids and PRP interventions are effective in improving pain, stiffness, and function in patients with bilateral knee osteoarthritis up to six months with no statistically significant difference between the two. To our knowledge, this is the first case of bilateral CGs diagnosed with a combination of CT, MRI, VO, and histopathology and removed minimal invasively via VO, without a need for ventral bulla osteotomy, which led to complete remission of all signs and no relapse until the follow up 6 months later.
  • ||||||||||  triamcinolone acetonide / Generic mfg.
    Journal:  The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma. (Pubmed Central) -  Nov 4, 2022   
    IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.
  • ||||||||||  dexamethasone / Generic mfg., deoxyglucose / Generic mfg.
    Preclinical, Journal:  Glucocorticoids decrease thermogenic capacity and increase triacylglycerol synthesis by glycerokinase activation in the brown adipose tissue of rats. (Pubmed Central) -  Nov 4, 2022   
    Despite promoting a decrease in the incorporation of U-[ C]-glycerol into triacylglycerol (~54%), dexamethasone increased the content (~55%) and activity (~41%) of glycerokinase without affecting glucose uptake or glyceroneogenesis. Our data suggest that glucocorticoid administration reduces IBAT thermogenesis through sympathetic inactivation and stimulates glycerokinase activity and content, contributing to increased generation of glycerol-3-P, which is mostly used to esterify fatty acid and increase triacylglycerol content promoting IBAT whitening.
  • ||||||||||  dexamethasone / Generic mfg., dexmedetomidine / Generic mfg.
    Journal:  Measures to prolong duration of sensory block after regional anaesthesia. (Pubmed Central) -  Nov 4, 2022   
    Both have few side effects and a favourable safety profile. However, a preferable duration of analgesia lasting for the first 24 h postoperatively is still not reliably achievable.
  • ||||||||||  dexamethasone / Generic mfg., ceftriaxone / Generic mfg., cefotaxime / Generic mfg.
    Journal, Real-world evidence:  Penicillin- and Cephalosporin-Resistant Pneumococcal Meningitis: Treatment in the Real World and in Guidelines. (Pubmed Central) -  Nov 4, 2022   
    High-dose CTX (300 mg/Kg/day) helped to treat failed or relapsed cases and protected against failure when used as empirical therapy (P = 0.02), even in CTX-resistant cases. High-dose CTX is a good empirical therapy option for pneumococcal meningitis in the presence of a high prevalence of penicillin and cephalosporin resistance, effectively treating pneumococcal strains with MICs up to 2 mg/L for either penicillin or CTX.