Hebron University

About: Hebron University is a education organization based out in Hebron, Palestinian Territory. It is known for research contribution in the topics: Population & Cancer. The organization has 2714 authors who have published 4180 publications receiving 163736 citations.

Clinical Management of Adverse Events Associated with Lorlatinib

Abstract: Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.

ADAM17 inhibition may exert a protective effect on COVID-19.

Abstract: During the last 2 months, a novel conoronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] infection or coronavirus disease 2019 (COVID-19) has been identified, producing a global threat leading to more than 40 598 deaths worldwide [1]. Recently, by genome sequencing and homology modelling, angiotensin-converting enzyme 2 (ACE2) has been found to be the receptor for SARS-CoV-2, despite amino acid variation at some key residues [2]. The extracellular domain of ACE2 was demonstrated as a receptor for the spike (S) protein of SARS-CoV [3]. ACE2 is predominantly expressed on the apical surface of well-differentiated airway epithelia, especially ciliated cells [4, 5]. Since a virus must attach to and enter cells before it can replicate, surface expression of ACE2 and the state of cell differentiation may directly influence SARS-CoV disease pathogenesis [4]. ADAM17 is a disintegrin and metalloproteinase domain 17 that was initially described in 1997 by Black et al. to specifically cleave the precursor of tumour necrosis factor a (pro-TNF-a) [6]. It is already known that ADAM17 can also release the ectodomains of a diverse variety of membraneanchored cytokines, cell adhesion molecules, receptors, ligands and enzymes, such as ACE2 [7]. ACE2 shedding by ADAM17 was first described by Lambert et al. by experiments performed using human embryonic kidney cells (HEK293) expressing human ACE2 (HEK-ACE2) in 2005 [7]. Under phorbol myristate acetate stimulation, the ACE2 protein detected on western blot analysis changed from a polypeptide of 120 kDa to a polypeptide of 105 kDa showing a proteolytic shedding occurring in the extracellular juxtamembrane region and releasing an enzymatic active ectodomain [7]. The authors developed distinct techniques to detect the main proteinase responsible for this proteolytic shedding event. First, incubation of HEK-ACE2 cells with TNF-a protease inhibitor 1 (TAPI-1), a hydroxamic acid-based metalloproteinase inhibitor, helped to detect ADAM17 as the main enzyme responsible for ACE2 shedding. Secondly, the use of natural inhibitors of metalloproteinases such as TIMP-3 also showed a reduced stimulated ADAM17 shedding activity. Finally, the confirmation was made using small interfering RNA (siRNA) to reduce the expression of ADAM17. Analysis of media proteins collected following incubation of transfected cells demonstrated an associated decrease in stimulated ACE2 shedding. These studies suggested that the up-regulation of ACE2 shedding could modulate high levels of shed ACE2, which could inhibit the infectivity of the SARS virus [7]. In the same line, Jia et al. [4] demonstrated that ACE2 sheds from differentiated primary airway epithelial cells and Calu-3 cell line. When SARS S protein pseudovirions were applied to HEK cells transfected with wildtype ACE2, SARS-CoV S was efficiently transduced. In contrast, when ACE2-SEC (containing the entire ACE2 ectodomain fused to the secretion signal peptide of the human b-defensin 2 gene) and ACE2-DRBD (containing alanine substitution mutations that allow the interaction with SARS-S) were cotransfected into HEK293 cells, the transduction efficiency of S protein-pseudotyped virions failed to increase, demonstrating that ACE2 must be cell-associated to serve as a coronavirus receptor, and that soluble ACE2 (sACE2) competes for S protein binding [8]. However, there are some controversies regarding the role of ADAM17 and sACE2 during virus infection. In that sense, in 2008, Haga et al. found that SARS-S induced ADAM17dependent shedding of ACE2 and also that the process was coupled with TNF-a production. They demonstrated that mutation in the cytoplasmic tail of ACE2 inhibited its shedding and reduced viral infection, and ACE2 or ADAM17 silencing blocked viral infection. Interestingly, mutants of cytoplasmic ACE2 were unable to activate either ACE2 shedding or TNF-a production, or even SARS-S binding. From these findings, they suggested that ADAM17 activity is modulated by the cytoplasmic tail of ACE2, facilitating both virus entry and tissue damage through TNF-a. However, the authors do not specify the intracellular pathway activated by the intracellular domain of ACE2 [9]. The authors postulated that ACE2 is down-regulated after viral infection because ACE2 shedding increases. However, administration of TAPI-0 and ADAM17 siRNA inhibited ACE2 shedding, while introduction of ADAM17 cDNA recovered SARS-S-induced shedding. Finally, this study also showed that ADAM17 siRNA reduced SARS-CoV infection, indicating that ADAM17 plays an important role in the entry of SARSCoV. It is unclear how ADAM17 facilitates viral entry. However, it seems that the peptidase activity would be critical

Endovascular Thrombectomy for Mild Strokes: How Low Should We Go?

Abstract: Background and Purpose- Endovascular thrombectomy (EVT) is effective for acute ischemic stroke with large vessel occlusion and National Institutes of Health Stroke Scale (NIHSS) ≥6. However, EVT benefit for mild deficits large vessel occlusions (NIHSS, <6) is uncertain. We evaluated EVT efficacy and safety in mild strokes with large vessel occlusion. Methods- A retrospective cohort of patients with anterior circulation large vessel occlusion and NIHSS <6 presenting within 24 hours from last seen normal were pooled. Patients were divided into 2 groups: EVT or medical management. Ninety-day mRS of 0 to 1 was the primary outcome, mRS of 0 to 2 was the secondary. Symptomatic intracerebral hemorrhage was the safety outcome. Clinical outcomes were compared through a multivariable logistic regression after adjusting for age, presentation NIHSS, time last seen normal to presentation, center, IV alteplase, Alberta Stroke Program early computed tomographic score, and thrombus location. We then performed propensity score matching as a sensitivity analysis. Results were also stratified by thrombus location. Results- Two hundred fourteen patients (EVT, 124; medical management, 90) were included from 8 US and Spain centers between January 2012 and March 2017. The groups were similar in age, Alberta Stroke Program early computed tomographic score, IV alteplase rate and time last seen normal to presentation. There was no difference in mRS of 0 to 1 between EVT and medical management (55.7% versus 54.4%, respectively; adjusted odds ratio, 1.3; 95% CI, 0.64-2.64; P=0.47). Similar results were seen for mRS of 0 to 2 (63.3% EVT versus 67.8% medical management; adjusted odds ratio, 0.9; 95% CI, 0.43-1.88; P=0.77). In a propensity matching analysis, there was no treatment effect in 62 matched pairs (53.5% EVT, 48.4% medical management; odds ratio, 1.17; 95% CI, 0.54-2.52; P=0.69). There was no statistically significant difference when stratified by any thrombus location; M1 approached significance ( P=0.07). Symptomatic intracerebral hemorrhage rates were higher with thrombectomy (5.8% EVT versus 0% medical management; P=0.02). Conclusions- Our retrospective multicenter cohort study showed no improvement in excellent and independent functional outcomes in mild strokes (NIHSS, <6) receiving thrombectomy irrespective of thrombus location, with increased symptomatic intracerebral hemorrhage rates, consistent with the guidelines recommending the treatment for NIHSS ≥6. There was a signal toward benefit with EVT only in M1 occlusions; however, this needs to be further evaluated in future randomized control trials.