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1.
Biuletyn Wydzialu Farmaceutycznego Warszawskiego Uniwersytetu Medycznego ; 20(2):1-23, 2022.
Article in Polish | EMBASE | ID: covidwho-2067785

ABSTRACT

A key part of many chronic diseases is inflammation controlled by inflammatory mediators. Regulation of their function allows muting the inflammatory response, which is the desired effect in the treatment of inflammatory diseases. The source of mediators is arachidonic acid, converted to pro-inflammatory mediators by cyclooxygenases (COX) or lipooxygenases (LOX). The 5-LOX pathway is full of target points for the regulation of biosynthesis of cysteinyl leukotrienes (CysLT) - one of the major classes of inflammatory mediators. These compounds exert their activity through specific leukotriene receptors - first (CysLT1R) and second (CysLT2R). Drugs that inhibit CysLT synthesis, as well as leukotriene receptor antagonists (LTRA), form a group of drugs known as anti-leukotriene drugs. Currently, only a few representatives of this group are available in the pharmacies around the world: The 5-LOX inhibitor - zileuton - and three CysLT1R antagonists - montelukast, pranlukast, and zafirlukast. LTRAs due to their wide range of anti-inflammatory effects are a group of drugs with a high potential in the treatment of inflammatory diseases. The study of new applications of known LTRAs and the search for new members of the LTRA group are the main directions of development in this field of pharmacy. This work summarizes the benefits of using anti-leukotriene drugs in the treatment of chronic diseases and presents new directions for using LTRAs.

2.
Acta Medica Peruana ; 39(2):151-165, 2022.
Article in Spanish | EMBASE | ID: covidwho-2067671

ABSTRACT

The Janus-Kinase signal transducer and the transcription activation pathway known as JAK / STAT is a major signaling pathway for the transduction of information in many inflammatory cytokines involved during sepsis. The JAK / STAT pathway has been shown to be strongly related to multiorgan failure, and many cytokines can exert their biological effects through this pathway. In recent years, considerable progress has been made in understanding functions of this complex;however, its role in sepsis as a therapeutic target remains under experimentation. This review describes the specific functions of the JAK / STAT pathway, its role in sepsis, and presents a translational approach to the therapeutic perspective aiming to inhibit this signaling pathway during sepsis and its interaction with inflammatory diseases such as COVID-19. Copyright © 2022 by Begell House, Inc.

3.
American Journal of Transplantation ; 22(Supplement 3):1102, 2022.
Article in English | EMBASE | ID: covidwho-2063518

ABSTRACT

Purpose: Vaccination against SARS-CoV-2 is essential. Complicating this effort are reports of a suboptimal response to the SARS-CoV-2 spike protein in patients on immunosuppressive medications and possible thrombotic microangiopathy (TMA) in renal transplant patients who receive the mRNA type vaccines. Method(s): 48 year old male with end stage renal disease who received a living unrelated transplant in 2015. Pre-operative creatinine was 10.42 mg/dL and decreased to 2.48 mg/dL within a week. Patient received Basiliximab induction and maintained on tacrolimus and mycophenolate (MMF). One month post-transplant patient was diagnosed with TMA. Tacrolimus was stopped and patient was switched to Sirolimus and continued on MMF. Patient was followed closely by transplant nephrology for the next 5 years with a baseline creatinine of 1.9 mg/dL, protein to creatinine ratio below 0.5 mg/mg and well controlled diabetes. No DSA Class I or II detected on regular testing. Patient was compliant with all prescribed medications. On January 25 2021 patient received Pfizer Vaccine. Second Pfizer vaccine administered on February 18 2021. A week later creatinine was noted to be 3.44 mg/dL. Repeat creatinine of 4.27 mg/dL. Biopsy revealed diffuse lymphocytic interstitial inflammation, peritubular capillaritis, and C4D negative. Findings consistent with chronic TMA. DSA testing revealed Class II DSA:DQ2 (SI-5933), Allosure 1.2 %. BK < 500 and CMV undetected. Patient received therapeutic plasma exchange, IV Ig infusion and steroids while on MMF and sirolimus. His creatinine decreased to 2.9 mg/dL on discharge. Over the next 6 months graft function deteriorated. He is now CKD stage 5 and under evaluation for a second transplant. Result(s): There are case reports of COVID-19 vaccine administration and transplant graft dysfunction. A possible mechanism involves the mRNA lipid nanoparticleencapsulated platform producing such a robust CD4 and CD8 T-cell response that pro-inflammatory cytokines are activated or that immune complex associated glomerular disease occurs resulting in the development of TMA in susceptible patients. Conclusion(s): A possible link between SARS CoV-2 vaccination and kidney transplant TMA warrants the implementation of close surveillance of vaccinated transplant patients, particularly susceptible individuals. More research is needed to determine if this link exists.

4.
American Journal of Transplantation ; 22(Supplement 3):443, 2022.
Article in English | EMBASE | ID: covidwho-2063389

ABSTRACT

Purpose: SARS CoV-2 vaccination elicits both robust humoral and T-cell immune responses in healthy individuals. However, a comprehensive assessment of immune responses to SARS-CoV-2 vaccination in renal allograft recipients is variable and dependent primarily on Spike IgG levels. Here, we analyzed the humoral and T-cell responses in vaccinated transplant recipients. Method(s): 61Tx patients maintained either on Tacrolimus (TAC, 32) or Belatacept (BELA, 29) who were greater than one month post 2nd dose of the Pfizer BNT162b2, and 41 healthy individuals were enrolled. Fresh whole blood was incubated with SARS CoV-2 Spike peptides pool and the activated CD4+ (IL-2/TNF-alpha)+ and CD8+ (TNF-alpha/IFN-gamma)+ T cells were enumerated by flow cytometry and defined as CoV-2-specific T cells. Plasma was analyzed for Spike Receptor Binding Domain (RBD)-specific IgG by ELISA. The Spike RBD-specific IgG levels and Spikespecific CD4+/CD8+ T-cell immune responses were analyzed in TAC- and Bela- Tx patients along with healthy controls. Result(s): Our data demonstrated poor Spike IgG and T cell immune responses in Tx patients1M post-2nd dose of vaccine (21% v. 93% in positive Spike IgG and 37% v. 88% in positive T cell responses, Tx v. controls, respectively). However, 34% of Spike IgG (-) patients demonstrated positive CD4+ and/or CD8+ T-cell immune responses. No significant difference in T cell immunity was found between TAC and BELA treated patients. Conclusion(s): Immunocompromised Tx patients demonstrated significant defects in humoral and T cell immune response after vaccination. Patients maintained on TAC v. BELA demonstrated similar depressions in immune responses post-vaccination. 34% of vaccinated Tx patients, demonstrated Spike-specific T cell immunity despite being Spike IgG negative. This is suggestive of a divergent immune response with dominant cellular immunity. These observations are important since activation of T-cell immunity early after exposure to SARS-CoV2, while not preventing infection will likely modify severity of disease. (Table Presented).

5.
American Journal of Transplantation ; 22(Supplement 3):441-442, 2022.
Article in English | EMBASE | ID: covidwho-2063342

ABSTRACT

Purpose: Correlates of protection for SARS-CoV-2 vaccines are not well-established in kidney transplant recipients(KTRs). Studies have highlighted the importance of neutralizing antibodies(Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity, T and B cell response in KTRs following SARS-CoV-2 vaccination. Method(s): KTRs eligible for SARS-CoV-2 vaccination from 3/12/21 were enrolled. Baseline and weekly blood samples were collected for routine lab, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells post-vaccination. Result(s): 49 KTRs were enrolled ( Demographics -Table 1). 10 patients (20.4%) mounted an Ab response following vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV- 2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Fig 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naive participants (P = 0.09 for SARS-CoV-2-naive, P=0.03 for SARS-CoV-2-experienced adults, Fig 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naive patients only (Fig 1A-D). Conclusion(s): Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients irrespective of history of COVID-19. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigenspecific or confer immunity. (Table Presented).

6.
Chest ; 162(4):A1866, 2022.
Article in English | EMBASE | ID: covidwho-2060877

ABSTRACT

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Interstitial pneumonitis (ILD) is inflammation of lung interstitium leading to scarring and pulmonary fibrosis. Various etiologies include idiopathic, connective tissue disorders, sarcoidosis and drug induced1. Many chemotherapy agents have been implicated in drug related ILD such as bleomycin, taxanes. However, newer chemotherapeutic drugs such as molecular agents such as anti-VEGF, anti-EGFR (panitumumab) could be causative of drug induced ILD. CASE PRESENTATION: A 75-year-old female with stage IV sigmoid colon cancer treated with surgery, adjuvant FOLFOX chemotherapy and Panitumumab. She presented to the emergency department with shortness of breath and hypoxia after known COVID-19 exposure. Initial imaging with chest radiography showed bilateral ground glass opacities. A chest CT pulmonary embolism protocol was negative for pulmonary embolism but showed bilateral ground glass opacities (GGOs) and some interstitial thickening (L>R) not typical of COVID-19 infection. She was treated with remdesivir and dexamethasone, however her oxygen requirements continued to rapidly escalate. A repeat CT chest without contrast showed bilateral asymmetric interstitial thickening and GGOs. Given persistence of CT chest abnormalities, workup for interstitial lung disease was initiated. The results include ANA titer 1:80, otherwise negative ANCA profile, rheumatoid factor, anti-CCP, Scl-70, Sjogren antibodies. Given clinical history and imaging findings, diagnosis of ILD was suspected, and she was started on solumedrol 1 mg/kg. Her oxygen requirements decreased significantly over the next 2 days, and she was discharged home on oral steroid taper and pneumocystis pneumonia prophylaxis. DISCUSSION: Panitumumab is a fully humanized monoclonal antibody against EGFR. Approved by the US Food and Drug Administration in 2006 for advanced or recurrent colorectal cancer exhibiting wild-type KRAS mutation.2 ILD is rarely reported with panitumumab monotherapy, but higher incidence when used as a combination treatment such as with FOLFOX or FOLFIRI. A Japanese post-marketing surveillance study from 2010-2015 showed an ILD incidence of 1.3% but mortality rates of 51.3%.2 EGFR is expressed on basal cells and non-cilia cells of the bronchioles and type II cells of the alveolus. EGFR mediated mechanisms are important in tissue repair.3 Therefore inhibition of this pathway has been postulated to play a role in development of ILD. Another mechanism was decreased surfactant production by type II cells in pre-clinical study.4,5 ILD secondary to Panitumumab can occur at any point during therapy and up to 1 year after administration of drug.6 The role of infectious processes, in this case, COVID-19 pneumonia, could synergistically worsen ILD presentation. CONCLUSIONS: Although the incidence of ILD is low, the mortality rate is high, therefore early recognition and treatment is associated with improved clinical outcomes. Reference #1: Mudawi D, Heyes K, Hastings R, Rivera-Ortega P, Chaudhuri N. An update on interstitial lung disease. Br J Hosp Med (Lond). Jul 2 2021;82(7):1-14. Reference #2: Osawa M, Kudoh S, Sakai F, et al. Clinical features and risk factors of panitumumab-induced interstitial lung disease: a postmarketing all-case surveillance study. Int J Clin Oncol. Dec 2015;20(6):1063-1071. Reference #3: The FASEB Journal - 2000 - Puddicombe - Involvement of the epidermal growth factor receptor in epithelial repair in asthma.pdf. DISCLOSURES: No relevant relationships by Navitha Ramesh No relevant relationships by Uba Udeh

7.
Chest ; 162(4):A1415, 2022.
Article in English | EMBASE | ID: covidwho-2060814

ABSTRACT

SESSION TITLE: Problems in the Pleura Case Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment of a variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL). There is an association of increased risk of bleeding with ibrutinib due to platelet dysfunction caused by the medication. Bleeding is usually non-life threating such as subcutaneous or mucosal bleeding, epistaxis, and ecchymosis. But major bleeding has been reported such as intracranial hemorrhage and gastrointestinal hemorrhage. Thoracic complications from ibrutinib are rare. Below is a case report discussing a hemorrhagic pleural effusion thought to be caused by Ibrutinib. CASE PRESENTATION: Patient is a 78-year-old male initially diagnosed with CLL on flow cytometry showing a low-grade B cell lymphoproliferative process. Patient was monitored by Hematology and when kappa light chain numbers began to rise, a bone marrow biopsy was performed showing 90% infiltration of the marrow with lymphoid cells. Patient was started on Ibrutinib therapy and responded well to treatment. A year after starting therapy, patient presented to the emergency room with increased shortness of breath and fatigue. Patient was found to be COVID-19 positive and chest x-ray showed a large right sided pleural effusion. Thoracentesis was performed draining 1650cc of bloody fluid. Fluid studies revealed a lymphocytic effusion with RBC count 1,185375, WBC of 1751. Cultures and cytology were negative. On further history, patient was without recent trauma or surgery, CTA chest was negative for pulmonary embolism. QuantiFERON Gold test was negative, indicating low likelihood of tuberculosis. Patient was not on any antiplatelet or systemic anticoagulation medications. Ibrutinib therapy was held during hospitalization and pleural effusion did not reaccumulate. Patient passed away during hospital stay secondary to respiratory failure due to COVID-19. DISCUSSION: Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib predisposes to bleeding by inhibiting BTK and Tec, which play a role in the inhibitory signaling pathway of platelet collagen receptors such as glycoprotein VI (GP VI) and C-type lectin-like receptor 2 (CLEC-2). Our patient had no other risk factors for developing a hemorrhagic effusion. CLL itself can cause malignant effusions, one study found the incidence of malignant effusions among patients with CLL to be 9%, but the effusion was noted to be serous or serosanguinous and there was pleural involvement in all patients which was not the case in our patient. CONCLUSIONS: There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. It is important to realize bleeding complications related to ibrutinib therapy can occur. Reference #1: Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835-847. doi:10.1111/jth.13651 Reference #2: Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388 Reference #3: Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56-63. doi:10.1016/j.critrevonc.2019.02.001 DISCLOSURES: No relevant relationships by fatima ali No relevant relationships by Joan Wiley

8.
Chest ; 162(4):A1128-A1129, 2022.
Article in English | EMBASE | ID: covidwho-2060777

ABSTRACT

SESSION TITLE: Imaging, ECMO, and other Procedures in the ICU Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Superior sagittal sinus (SSS) thrombosis is a rare cause of stroke that is difficult to identify due to various clinical presentations. It is the most common form of dural sinus thrombosis, and common risk factors include hypercoagulable state, traumatic head injury, pregnancy/postpartum, and malignancy. More than 85 percent of adult patients have at least one risk factor for cerebral venous thrombosis. Some patients with SSS thrombosis do not have clearly identifiable risk factors, and this case highlights one such patient. CASE PRESENTATION: A 60-year-old Caucasian male with hypertension, hyperlipidemia, and a recent intracranial hemorrhage with residual left-sided weakness, presented to the emergency department with worsening left-sided weakness. Upon admission, his physical exam was notable for 4/5 strength in the left upper extremity and 2/5 strength in the left lower extremity. This was a reduction in strength from a baseline of 4/5 in the left upper and lower extremities. Labs on admission were normal except for high-sensitivity troponin of 86 and WBC of 14.5. UA with a small amount of blood. An initial CT brain without contrast showed no acute changes, evolutionary changes in the right frontal temporal lobe, and subtle curvilinear hyperdensity near a site of the intracranial hemorrhage identified in the prior month. This curvilinear hyperdensity was thought to reflect early parenchymal calcification. MRI brain without contrast showed new and evolving areas of abnormal signaling and an evolving hematoma with surrounding vasogenic edema, all of which are in the right lobe. There was no apparent diffusion coefficient correlate. Thus, MRI with contrast and MRV was recommended. EEG showed no evidence of epileptiform activity. Additionally, transthoracic echo demonstrated new non-ischemic cardiomyopathy with an EF of 35-40%. The diagnosis was ultimately made after the patient had a Magnetic Resonance Venography (MRV) which showed evidence of the SSS thrombosis and an indication that the previously visualized curvilinear hyperdensity is suspected to represent slowed flow within a surface vein. Heparin was started to recanalize the sinus and prevent thrombus propagation. After the appropriate treatment was started, the patient's weakness improved dramatically. DISCUSSION: Typically, patients with SSS thrombosis have identifiable risk factors like hypercoagulable states, traumatic head injuries, pregnancy/postpartum, malignancy, and more recently association with COVID-19 infection. In this case, since the patient lacked identifiable risk factors, the MRV played a key role in the diagnosis. CONCLUSIONS: Like our patient, 30-40 percent of patients present with an intracerebral hemorrhage. Differentials of SSS thrombosis should be considered in etiologies for intracerebral hemorrhage, especially when an identifiable cause is lacking, in order to avoid delays in treatment and resolution. Reference #1: Abdalkader M, Shaikh SP, Siegler JE, Cervantes-Arslanian AM, Tiu C, Radu RA, Tiu VE, Jillella DV, Mansour OY, Vera V, Chamorro Á, Blasco J, López A, Farooqui M, Thau L, Smith A, Gutierrez SO, Nguyen TN, Jovin TG. Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature. J Stroke Cerebrovasc Dis. 2021 Jun;30(6):105733. doi: 10.1016/j.jstrokecerebrovasdis.2021.105733. Epub 2021 Mar 4. PMID: 33743411;PMCID: PMC7931726. Reference #2: Rehman A, Husnain MG, Mushtaq K, Eledrisi MS. Cerebral venous sinus thrombosis precipitated by Graves’ disease. BMJ Case Rep. 2018 Jun 4;2018:bcr2017224143. doi: 10.1136/bcr-2017-224143. PMID: 29866676;PMCID: PMC5990097. Reference #3: Nakase H, Takeshima T, Sakaki T, Heimann A, Kempski O. Superior sagittal sinus thrombosis: a clinical and experimental study. Skull Base Surg. 1998;8(4):169-74. doi: 10.1055/s-2008-1058178. PMID: 17171061;PMCID: PMC1656696. DISCLOSURES: No relevant rel tionships by Ken Johnson No relevant relationships by Nina Le No relevant relationships by Riaz Mahmood No relevant relationships by Ngoc Phan

9.
Chest ; 162(4):A1040-A1041, 2022.
Article in English | EMBASE | ID: covidwho-2060759

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Malignant hyperthermia (MH) is a hypermetabolic crisis where an increase in carbon dioxide is seen despite an increased minute ventilation with a proposed mechanism as a disturbance in calcium homeostasis. Commonly seen in volatile anesthetic agents and depolarizing neuromuscular blockers, rarely with nondepolarizing agents. There has been one reported case of cisatracurium-induced MH in the setting of ARDS. There have been two cases reported of nondepolarizing neuromuscular agents causing MH in the setting of COVID-19. CASE PRESENTATION: A 34-year-old man with severe COVID-19 complicated by ARDS on ventilator day 16, due to refractory fevers, ventilatory dyssynchrony, high minute ventilation and auto-PEEP phenomena, the decision was made to attempt neuromuscular paralysis. After one dose of cisatracurium, the patient became hyperthermic and end-tidal carbon-dioxide increased from 58-98 with inability to oxygenate. The patient developed high peak pressures, bedside ultrasound revealed no evidence of pneumothorax also confirmed with chest x-ray. The patient then received a dose of dantrolene with end-tidal improving to 60 and tachycardia also resolved. A creatinine kinase level drawn was elevated at 571. DISCUSSION: A proposed mechanism of MH is calcium release from sarcoplasmic reticulum, a mutation in skeletal muscle ryanodine receptor calcium release channels that can release IL-6 when activated leading to excessive muscular contraction. Proinflammatory cytokine IL-6, dantrolene may block IL-6 release which results in its therapeutic effect in the treatment of MH. IL-6 has been used to predict deterioration from COVID-19. Dantrolene in this sense has been proposed as a potential therapeutic agent against COVID-19, inhibiting intracellular calcium influx thus preventing the pathological feedback of viral entry into cells via endocytosis, as this is a calcium dependent process. Given the possible link between IL-6 release, calcium and MH, SARS-CoV-2 viral entry into cells may place patients at higher risk of MH. Patients with COVID-19 may be at higher risk of MH, even in rare agents such as non-depolarizing agents as seen in this case. Awareness of this potentially increased complication from these agents in those patients with COVID-19 is key as we continue in the ongoing global pandemic. CONCLUSIONS: Given the possible link between IL-6 release, calcium and MH, SARS-CoV-2 viral entry into cells may place patients at higher risk of MH. Patients with COVID-19 may be at higher risk of malignant hyperthermia, even in rare agents such as non-depolarizing agents as seen in this case. Awareness of this potentially increased complication from these agents in those patients with COVID-19 is key as we continue in the ongoing global pandemic. Reference #1: Sathyanarayanan SP, Hamza M, Hamid K, Groskreutz D. Cisatracurium-Associated Malignant Hyperthermia During Severe Sars-CoV-2 Infection. Am J Ther. 2021 Aug 10;28(5):e590-e591. doi: 10.1097/MJT.0000000000001437. PMID: 34387563;PMCID: PMC8415506. Reference #2: Chiba N, Matsuzaki M, Mawatari T, Mizuochi M, Sakurai A, Kinoshita K. Beneficial effects of dantrolene in the treatment of rhabdomyolysis as a potential late complication associated with COVID-19: a case report. Eur J Med Res. 2021 Feb 8;26(1):18. doi: 10.1186/s40001-021-00489-8. PMID: 33557936;PMCID: PMC7868892. Reference #3: Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, Jiang Y, Cheng X, Zhu C, Xia Y. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020 Dec;9(1):1123-1130. doi: 10.1080/22221751.2020.1770129. PMID: 32475230;PMCID: PMC7473317. DISCLOSURES: No relevant relationships by Hira Bakhtiar No relevant relationships by Timothy DAmico no disclosure on file for Sarah Margolskee;No relevant relationships by Carlos Merino No relevant relationships by Joanna Moore

10.
Chest ; 162(4):A594, 2022.
Article in English | EMBASE | ID: covidwho-2060641

ABSTRACT

SESSION TITLE: Medications and Pulmonary Rehabilitation in COVID-19 Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: JAK-antagonists and IL-6 inhibitors are immunomodulators indicated for inflammatory pathologies. With the COVID pandemic, these drugs have been utilized in management of hospitalized patients with SARS-CoV-2. Selection between the two drug classes has been attributed to availability and physician comfort. No existing comparative randomized trial to date. METHODS: We performed a systematic review and network meta-analysis using PRISMA guidelines. Randomized controlled trials evaluating various IL-6 inhibitors and JAK-antagonists were included. Outcomes were 28-day mortality and progression, defined as advancement to mechanical ventilation or ECMO. Subgroup analysis of concomitant steroid and remdesivir usage was also analyzed. P-scores were used to rank treatment groups in class and drug specific classifications. RESULTS: We identified 33 RCTs with 13,680 patients that met our selection criteria. Our analysis revealed that IL-6 inhibitor versus JAK antagonists, IL-6 was associated with greater odds of mortality (OR = 1.23 (1.13, 1.34), p = 0.01). This finding was also evident in the subgroup receiving concomitant steroids and remdesivir (OR = 1.41 (1.00, 2.00), p = 0.049) but no significant differences observed for the outcome of progression in this group. Baricitinib is associated with a significant 30% reduction in 28-day mortality compared to Tocilizamab CONCLUSIONS: JAK-a vs control and IL-6 inhibitors vs control exhibit mortality reducation but JAKs did so at a greater rate. Similarly, for drug specific comparisons, Baricitinib reduced mortality by the greatest amount. Only IL-6 inhibitors seemed to have a significant effect on preventing progression. Siltuximab and Tocilizumab were both effective against control but Tocilizumab reduced progression the best. As a secondary goal, a sub-group analysis on concomitant steroid and Remdesivir usage demonstrated that for drug specific comparisons, Baricitinib performed better for reducing mortality & Tocilizumab continued to be the most effective in preventing progression. However, with Remdesivir and steroids, there was no significant difference between Baricitinib and Tocilizumab in decreasing mortality. This is contrary to the findings without steroids. CLINICAL IMPLICATIONS: We hope to use this data to help clinical decision making between JAK-a and IL-6 inhibitors which are currently being used interchangeably for the management of COVID-19 in hospitalized patients. Through our study results and analysis, we recommend that Baricitinib be used to decrease mortality rates and disease progression for the treatment of COVID-19 with concomitant therapy corticosteroids and Remdesivir. Moving forward with this data, we aim to help restructure COVID-19 treatment algorithms regarding IL-6 and JAK antagonists. DISCLOSURES: No relevant relationships by Monica Bhagavan No relevant relationships by rukhsaar khanam No relevant relationships by Anant Naik No relevant relationships by Aashka Shah

11.
Chest ; 162(4):A329, 2022.
Article in English | EMBASE | ID: covidwho-2060565

ABSTRACT

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: The COVID-19 pandemic has been full of obstacles for the medical field. Considerable advancements have been made, yet we continue to discover new associations with this novel virus. In this case, we discuss a patient who was hospitalized for COVID-19 on 7/18/2020 in the intensive care unit. He developed a persistent cough with hemoptysis several months after discharge and was found to have active tuberculosis. The COVID-19 pandemic has continued to raise concerns regarding the repercussions of this infection, and as this case shows, includes reactivation of latent tuberculosis infections (LTBI) in affected patients. CASE PRESENTATION: A 59-year-old Latino male never-smoker with a history of diabetes (A1c 8.4%) presented 07/18/2020 for complaints of shortness of breath and cough. At that time, he tested positive for COVID-19. He was escalated to the ICU and required intubation. During his hospitalization, he received remdesivir for 5 days and dexamethasone 6 mg daily for 10 days with taper prior to his discharge. He was able to be extubated and oxygen requirement decreased to 2 liters nasal cannula. Patient was subsequently discharged on 09/14/2020. He began developing a persistent cough with noted hemoptysis in 02/2021 and was referred to pulmonology at that time. High resolution CT scan of the chest was ordered and revealed thick-walled cavitary lesions of various sizes throughout both lungs although with an upper lobe predominance and tree-in-bud nodularity as well as tracheomegaly. AFB and QuantiFERON Gold assay were positive. Patient reported he had done multiple mission trips to endemic areas before COVID pandemic but had not been during the pandemic. Patient underwent quarantine and treatment for active tuberculosis. DISCUSSION: Tuberculosis reactivation results from previous latent bacteria that becomes active either from inducible factors or spontaneously. Risk factors for reactivation include HIV/AIDS, steroid use, diabetes, kidney disease, and smoking. [1] The primary basis of these risk factors is the immunosuppression conferred to the patient. COVID-19 has the potential to cause a disruption of the immune system which could predispose a patient to reactivation of LTBI. Studies have shown that defects or interference of the IFN-γ pathway can cause susceptibility to intracellular infections, including tuberculosis.[2] There may be an acquired disruption in this pathway caused by COVID-19, although more research is required. CONCLUSIONS: The COVID-19 pandemic has raised concerns for increased risk of reactivation of latent infection as well. In this case, the patient had multiple risk factors, but certainly a diagnosis of COVID-19 could weaken the immune system allowing for the reactivation of LTBI. This association will require more research to solidify. It is important, as seen in the case discussed above, to continue to be vigilant in diagnosis and treatment of our patients. Reference #1: Riley L. UpToDate. UpToDate – Evidence-based Clinical Decision Support ;Wolters Kluwer. Published September 15, 2021. Accessed February 2, 2022. https://www.uptodate.com/contents/tuberculosis-natural-history-microbiology-and-pathogenesis?search=tuberculosis&source=search_result&selectedTitle=4~150&usage_type=default&display_rank=4 Reference #2: Kampmann B, Hemingway C, Stephens A, et al. Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J Clin Invest 115: 2480-2488, 2005. DISCLOSURES: No relevant relationships by Steven Colby No relevant relationships by Radhika Shah

12.
Investigative Ophthalmology and Visual Science ; 63(7):3242-A0277, 2022.
Article in English | EMBASE | ID: covidwho-2058633

ABSTRACT

Purpose : Bacterial keratitis is a prevalent eye infection that causes corneal opacification and purulent discharge, especially among contact lens wearers. Such infections recruit innate immune cells into the cornea, predominately neutrophils (PMN). CD177 is a GPIanchored protein expressed on ∼50% of circulating PMN. Proteinase-3 (PR3) is a serine protease that binds CD177 and is shown to be released from PMN granules upon activation or expressed on the plasma membrane (mPR3). CD177 PMN can be protective or pathogenic in various diseases ranging from IBD to COVID-19. On the other hand, elevated PR3 is found in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis. With little known regarding the eye, this study investigates the expression and role(s) of CD177 and PR3 in the cornea following bacterial keratitis. Methods : This work uses an experimental model of bacterial keratitis carried out in 8-week-old, female susceptible C57BL/6 (B6) and resistant BALB/c mice. The left eye of each mouse was scarified then infected with P. aeruginosa ATCC strain 19660 (5 μL of 1 x 106 CFU). Corneas from naïve, uninfected mice from both strains served as controls. Corneas were harvested at 1, 3, and 5 days post-infection (p.i.). Levels of CD177 and PR3 were determined at the protein level by Western blot and by phenotypic profiling using flow cytometry. In vitro assessment was carried out using HL-60, a human promyelocytic cell line, and siCD177 knockdown. Results : Results from the in vivo model showed no differences in protein levels at 1 day p.i., but significantly higher levels of both CD177 and PR3 in B6 vs. BALB/c at 3 and 5 days p.i. Flow cytometry data revealed CD177+ and PR3+ expression on both PMN and macrophages from B6 and BALB/c infected corneas with differential mean fluorescence intensities detected between the strains under normal conditions and following infection. In vitro results indicated that cell activation was altered following CD177 knockdown with differences in downstream signaling. Conclusions : As one of the first studies to explore the role of CD177 and PR3 in the pathogenesis of bacterial keratitis, our findings reveal strain-specific expression profiles for PMN that may contribute to resistance vs. susceptibility. In addition, we show the presence of CD177 PR3 macrophages. Overall, these findings may uncover novel therapeutic targets to treat bacterial keratitis.

13.
Investigative Ophthalmology and Visual Science ; 63(7):1670-A0500, 2022.
Article in English | EMBASE | ID: covidwho-2058478

ABSTRACT

Purpose : Diabetes predisposes an individual to severe COVID-19. Diabetic cornea is also known to have impaired wound healing, increasing the chances of infection. Earlier, we reported the ability of SARS-CoV-2 to infect conjunctival cells, and the presence of viral RNA and proteins was also detected in the corneas of COVID-19 donors. In this study, we evaluated the effect of diabetes on corneal innate immune response during SARS-CoV-2 infection and sought to determine the underlying mechanisms. Methods : Human primary corneolimbal epithelial cells (HCECs) were isolated from the corneas of three diabetic and three non-diabetic donors. In vitro studies were performed by infecting HCECs with SARS-CoV-2-USA-WA1/2020 strain at MOI 0.5. Viral replication was assessed by viral genome copy number. RNAseq analysis was performed to determine genes/pathways altered by diabetic vs non-diabetic HCECs. qPCR was used to assess the expression of innate inflammatory and antiviral genes. Western blot was performed to detect the protein expression of antiviral signaling molecules. Results : The primary HCECs were found permissive to SARS-CoV-2 infection, as evidenced by increased viral replication which peaked at day 3 p.i. along with an induction of pSTAT1. Interestingly, HCECs from diabetic cornea had higher viral RNA on all three days post-infection. SARS-CoV-2 infected HCECs exhibited induced expression of inflammatory genes and their levels were relatively higher in diabetic cells. RNA-seq analysis revealed significant differences in diabetic vs. non-diabetic SARS-CoV-2 infected cells with alteration in genes regulating viral response, inflammation, and injury. The most affected down-regulated genes are related to lipid metabolism, ferroptosis, and oxidative stress. Conclusions : Our study demonstrates increased SARS-CoV-2 replication and differential innate antiviral and inflammatory response in HCECs from diabetic corneas. These results indicate that diabetes is a potential risk for enhanced infectivity of SARS-CoV-2 for the ocular surface.

14.
mBio ; 13(5): e0165022, 2022 10 26.
Article in English | MEDLINE | ID: covidwho-2053125

ABSTRACT

Bacteria have evolved many different signal transduction systems to sense and respond to changing environmental conditions. Signal integration is mainly achieved by signal recognition at extracytosolic ligand-binding domains (LBDs) of receptors. Hundreds of different LBDs have been reported, and our understanding of their sensing properties is growing. Receptors must function over a range of environmental pH values, but there is little information available on the robustness of sensing as a function of pH. Here, we have used isothermal titration calorimetry to determine the pH dependence of ligand recognition by nine LBDs that cover all major LBD superfamilies, of periplasmic solute-binding proteins, and cytosolic LBDs. We show that periplasmic LBDs recognize ligands over a very broad pH range, frequently stretching over eight pH units. This wide pH range contrasts with a much narrower pH response range of the cytosolic LBDs analyzed. Many LBDs must be dimeric to bind ligands, and analytical ultracentrifugation studies showed that the LBD of the Tar chemoreceptor forms dimers over the entire pH range tested. The pH dependences of Pseudomonas aeruginosa motility and chemotaxis were bell-shaped and centered at pH 7.0. Evidence for pH robustness of signaling in vivo was obtained by Förster Resonance Energy Transfer (FRET) measurements of the chemotaxis pathway responses in Escherichia coli. Bacteria have evolved several strategies to cope with extreme pH, such as periplasmic chaperones for protein refolding. The intrinsic pH resistance of periplasmic LBDs appears to be another strategy that permits bacteria to survive under adverse conditions. IMPORTANCE Demonstration of the pH robustness of extracytoplasmic sensing reveals a previously undescribed evolutionary mechanism that enables bacteria to monitor environmental changes under changing conditions. This mechanism includes the maintenance of the dimeric state of four-helixbundle ligand-binding domains (LBDs). The construction of biosensors is a rapidly growing field of research, and their use to monitor the progression of the COVID-19 pandemic has impressively demonstrated their usefulness. LBDs represent an enormous reservoir of binding modules that can be used to create novel biosensors. Among ligands recognized by LBDs are neurotransmitters, hormones, and quorum-sensing signals. The demonstration that extracytosolic LBDs bind their signals over a wide range of pH values will facilitate the design of biosensors that function under highly variable conditions of acidity and alkalinity.


Subject(s)
Bacterial Proteins , COVID-19 , Humans , Ligands , Bacterial Proteins/metabolism , Protein Binding , Pandemics , Chemotaxis , Bacteria/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Hormones/metabolism , Hydrogen-Ion Concentration
15.
Proteins ; 2022 Sep 16.
Article in English | MEDLINE | ID: covidwho-2034971

ABSTRACT

The heat shock protein 70 kDa (Hsp70) chaperone system serves as a critical component of protein quality control across a wide range of prokaryotic and eukaryotic organisms. Divergent evolution and specialization to particular organelles have produced numerous Hsp70 variants which share similarities in structure and general function, but differ substantially in regulatory aspects, including conformational dynamics and activity modulation by cochaperones. The human Hsp70 variant BiP (also known as GRP78 or HSPA5) is of therapeutic interest in the context of cancer, neurodegenerative diseases, and viral infection, including for treatment of the pandemic virus SARS-CoV-2. Due to the complex conformational rearrangements and high sequential variance within the Hsp70 protein family, it is in many cases poorly understood which amino acid mutations are responsible for biochemical differences between protein variants. In this study, we predicted residues associated with conformational regulation of human BiP and Escherichia coli DnaK. Based on protein structure networks obtained from molecular dynamics simulations, we analyzed the shared information between interaction timelines to highlight residue positions with strong conformational coupling to their environment. Our predictions, which focus on the binding processes of the chaperone's substrate and cochaperones, indicate residues filling potential signaling roles specific to either DnaK or BiP. By combining predictions of individual residues into conformationally coupled chains connecting ligand binding sites, we predict a BiP specific secondary signaling pathway associated with substrate binding. Our study sheds light on mechanistic differences in signaling and regulation between Hsp70 variants, which provide insights relevant to therapeutic applications of these proteins.

16.
Chinese Traditional and Herbal Drugs ; 53(15):4781-4794, 2022.
Article in Chinese | EMBASE | ID: covidwho-2033401

ABSTRACT

Objective To explore the application pattern and mechanism of medicine and food homologous traditional Chinese medicine (TCM) against modern viral diseases. Methods The method of literature mining was applied based on the characteristics of modern viral diseases, combining with ancient books and modern prescriptions for the prevention and treatment of viral diseases to build a relevant prescription database. Then SPSS and R language were used to analyze the high-frequency medicine and food homologous TCM and high confidence medicine and food homologous prescriptions in these prescriptions, and cluster analysis was carried out. The antiviral characteristic active ingredients of high-frequency medicinal and food homologous TCN were identified and analyzed, and the action mechanism of active ingredients against modern viral diseases was evaluate by network pharmacology. Results In the prevention and treatment of modern viral diseases, Gancao (Glycyrrhizae Radix et Rhizoma)-Chenpi (Citri Reticulatae Pericarpium)-Fuling (Poria) had the highest confidence, Glycyrrhizae Radix et Rhizoma-Jiegeng (Platycodonis Radix) had the highest support. At the same time, the prescriptions were clustered and analyzed to obtain Jinyinhua (Lonicerae Japonicae Flos)-Huangqi (Astragali Radix)-Huoxiang (Agastache rugosa), Glycyrrhizae Radix et Rhizoma-Xingren (Armeniacae Semen Amarum)-Poria-Platycodonis Radix-Citri Reticulatae Pericarpium, Ganjiang (Zingiberis Rhizoma)-Renshen (Ginseng Radix et Rhizoma), Zisu (Perilla frutescens)-Gegen (Puerariae Lobatae Radix), Lugen (Phragmitis Rhizoma)-Sangye (Mori Folium), Shengjiang (Zingiberis Rhizoma Recens)-Dazao (Jujubae Fructus) clustering new prescription. The core action targets of EGFR, CASP3, VEGFA, STAT3, MMP9, HSP90AA1, mTOR, PTGS2, MMP2, TLR4, MAPK14, etc were identified. The action mechanism involved human cytomegalovirus infection, coronavirus disease-coronavirus disease 2019 (COVID-19), etc. The core action pathway were phosphatidylinositol-3/kinase protein kinase B (PI3K/Akt) signal pathway, mitogen activated protein kinase (MAPK) signal pathway, interleukin-17 (IL-17) signal pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal pathway, etc. Conclusion Through data mining, six new prescriptions for preventing and controlling modern viral diseases were obtained, and the mechanism of action was preliminarily discussed, which provided some reference for the research and development of medicine and food homologous TCM prescriptions for the prevention and treatment of viral epidemics and related health products.

17.
Iranian Journal of Pharmaceutical Research ; 21(1), 2022.
Article in English | EMBASE | ID: covidwho-2033387

ABSTRACT

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

18.
HemaSphere ; 6:2239-2240, 2022.
Article in English | EMBASE | ID: covidwho-2032132

ABSTRACT

Background: Mantle cell lymphoma (MCL) is a B-cell tumor which often relapses. BCR inhibitors (Ibrutinib, Acalabrutinib) and antiapoptotic BCL2-family members blockers BH3-mimetics (Venetoclax, ABT-199) are effective drugs to fight MCL. However, the disease remains incurable, due to therapy resistance, even to the promising Venetoclax and Ibrutinib combination. Therefore, there is a profound need to explore novel useful therapeutic targets. CK2 is a S/T kinase overexpressed in several solid and blood tumors. We demonstrated that CK2, operating through a 'non-oncogene addiction' mechanism promotes tumor cell survival, and counteracts apoptosis, by activating pro-survival signaling cascades, such as NF-κ B, STAT3 and AKT. CK2 could regulate also BCL2 family members. The CK2 chemical inhibitor CX-4945 (Silmitasertib, Sil) is already under scrutiny in clinical trials in relapsed multiple myeloma, solid tumors and COVID-19. Aims: In this work, we tested the effect of CK2 chemical inhibition or knock down on Venetoclax (Ven)-induced cytotoxicity in MCL pre-clinical models to effectively reduce MCL cell growth and clonal expansion. Methods: CK2 expression and BCR/BCL2 related signaling components were analyzed in MCL cells and control cells by Western blotting. CK2 and BCL2 inhibition was obtained with Sil and Ven, respectively and with CK2 gene silencing through the generation of anti-CK2 shRNA IPTG-inducible MCL cell clones. Survival, apoptosis, mitochondrial membrane depolarization and proliferation were investigated by FACS analysis of AnnexinV/PI and JC-10 staining. The synergic action of Ven and Sil was analyzed by the Chou-Talalay combination index (CI) method. CK2 knock down in vivo was obtained in xenograft NOD-SCID mouse models Results: CK2 inactivation (with Sil or CK2 silencing) determined a reduction in the activating phosphorylation of S529 p65/RelA and S473 and S129 AKT, important survival cascades for MCL. Sil or CK2 silencing caused BCL2 and related MCL1 protein reduction, causing cell death. Importantly, we confirmed these results also in an in vivo xenograft mouse model of CK2 knockdown in MCL. Sil +Ven combination increased MCL cell apoptosis, as judged by the augmented frequency of Annexin V positive cells and expression of cleaved PARP protein, and JC-10 mitochondrial membrane depolarization, with respect to the single treatments. Captivatingly, Sil or CK2 gene silencing led to a substantial reduction of the Ven-induced increase of MCL-1, potentially counteracting a deleterious Ven-induced drawback. Analysis of cell cycle distribution confirmed an increased frequency of apoptotic cells in the sub G1 phase in CK2-silenced cells and a modulation of the other phases of the cell cycle. Remarkably, the calculated CI less than 1 suggested a strong synergic cell-killing effect between Sil and Ven, on all the cell lines tested, including those less sensitive or resistant to Ven Summary/Conclusion: We demonstrated that the simultaneous inhibition/knock down of CK2 and BCL2 synergistically cooperates in inducing apoptosis and cell cycle arrest of MCL malignant B-lymphocytes and has the potential of reducing MCL clonal growth, also counterbalancing mechanism of resistance that may arise with Ven. Therefore, CK2 is a rational therapeutic target for the treatment of MCL to be tested in combination with Ibrutinib or Ven.

19.
HemaSphere ; 6:1149-1150, 2022.
Article in English | EMBASE | ID: covidwho-2032119

ABSTRACT

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

20.
HemaSphere ; 6:1922-1923, 2022.
Article in English | EMBASE | ID: covidwho-2032111

ABSTRACT

Background: Patients with relapsed/refractory follicular lymphoma (R/R FL) often experience multiple relapses and require various lines of therapy. The ELARA and ZUMA-5 trials demonstrated high response rates along with acceptable safety profiles. We perform a phase 1b/2 single-center clinical trial of autologous point-of-care (POC) academic anti-CD19 chimeric antigen receptor (CAR) T-cells for patients with R/R FL treated with at least 2 lines of systemic therapy (NCT02772198). Aims: To report outcomes of POC CAR T-cell therapy in patients with R/R FL. Methods: Adults with R/R FL underwent a single leukapheresis procedure. Fresh peripheral blood mononuclear cells were isolated, activated, and transduced with a gammaretrovirus encoding for a CD19 CAR (based on an FMC63-derived ScFv, a CD28 costimulatory domain, and a CD3-ζ signaling domain). Lymphodepletion included fludarabine 25 mg/m2 over 3 days (days-4 to-2) and cyclophosphamide 900 mg/m2 once (day-2), followed by infusion of 1×106/kg CAR T-cells in the inpatient setting. Primary endpoints were response (by PET-CT, per Lugano criteria) at day 28, best response, and safety. Secondary endpoints included overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was as of 02/2022. Results: All 19 patients enrolled received CAR T-cell infusion in a median of 11 days (IQR 10-11) after leukapheresis. The median age was 61 years (IQR 52-66). Five (26%) patients had Karnofsky performance status < 90%. Disease stage at enrollment was III-IV in 16 (84%) patients. Two (11%) patients had bulky disease;8 (42%) had LDH > upper limit of normal;and 16 (84%) had Follicular Lymphoma International Prognostic Index ≥ 3. Disease status at enrollment was progressive disease (n=14, 74%), stable disease (n=3, 16%), or partial response (PR;n=2, 11%). Twelve patients (64%) were refractory to last treatment. Disease grade at most recent lymph node biopsy was 1 (n=3, 16%), 2 (n=11, 58%), or 3a (n=5, 26%). The median time from FL diagnosis was 3.9 years (IQR 2.5-4.6). Sixteen (84%) patients had progression of disease within 24 months of initial therapy. The number of prior therapies was ≥ 4 in 6 (32%) patients;and 5 (26%) patients underwent prior autologous transplantation. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 1 (5%) and 4 (21%) patients, respectively. One patient was infected with COVID-19 on the 5th day following cell infusion and was admitted to the intensive care unit. One patient had grade 3 atrial fibrillation. Severe neutropenia (absolute neutrophil count <500/μL), thrombocytopenia (platelets <50K/μL) and anemia (hemoglobin <10g/dl) occurred in 15 (79%), 5 (26%), and 7 (37%) patients, respectively. No bleeding events or death were recorded following cell infusion. Response was evaluated in all patients. Overall response rate on day 28 was 84% (79% complete response [CR]). One patient with PR on day 28 achieved a CR after a year of follow-up. Three patients (16%) continued to progress following CAR infusion. All patients were alive at the last follow-up (median follow-up, 11.5 months [IQR 4-21]). One-year PFS was 74% (95% CI, 53-100). The median duration of response (DOR) was not reached (95% CI, 12.5-not reached). Estimated DOR at 1-year was 89% (95% CI, 71-100). Image: Summary/Conclusion: Point-of-Care anti-CD19 CAR T-cell therapy, performed following a very short production time, induced high CR rate with an acceptable safety profile in a cohort of patients with high-risk R/R FL.

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