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Mariana Castells - One of the best experts on this subject based on the ideXlab platform.
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hypersensitivity reactions to therapeutic monoclonal antibodies phenotypes and endotypes
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: Ghislaine Annie C Isabwe, Marlene Garcia Neuer, Leticia De Las Vecillas Sanchez, Donnamarie Lynch, Kathleen Marquis, Mariana CastellsAbstract:Background The increasing use of mAbs has led to a rise in hypersensitivity reactions (HSRs), which prevent their use as first-line therapy. HSRs' symptoms, diagnostic tools, and directed management approaches have not been standardized. Objective We propose a novel evidence-based classification of HSRs to mAbs, based on the clinical phenotypes, underlying endotypes and biomarkers, as well as their management with Desensitization. Methods Phenotypes, endotypes, and biomarkers of HSRs to 16 mAbs for 104 patients were described and compared with the outcomes of 526 subcutaneous and intravenous Desensitizations. Results Initial reactions presented with 4 patterns: type I–like reactions (63%), cytokine-release reactions (13%), mixed reactions (21%), and delayed type IV reactions (3%). In contrast, of the 23% breakthrough HSRs during Desensitization, 52% were cytokine-release reactions, 32% were type 1, 12% were mixed, and 4% were type I with delayed type IV. Skin testing to 10 mAbs in 58 patients was positive in 41% of patients. Serum tryptase was elevated in 1 patient and IL-6 was elevated in 8 patients during Desensitization and was associated with a cytokine-release phenotype. Conclusions HSRs to mAbs can be defined as type I, cytokine-release, mixed (type I/cytokine-release), and type IV reactions, which are identified by biomarkers such as skin test, tryptase, and IL-6. These phenotypes can be used to improve personalized and precision medicine when diagnosing HSRs to mAbs and providing management recommendations with Desensitization. Desensitization provides a safe and effective retreatment option to remain on culprit mAbs as first-line therapy.
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Desensitization regimens for drug allergy state of the art in the 21st century
Clinical & Experimental Allergy, 2011Co-Authors: Laura B Fanning, David E Sloane, H Chong, James Fernandez, Maria Del Carmen Sanchoserra, Mariana CastellsAbstract:Summary Adverse reactions to drugs are increasingly being recognized as important contributions to disease in their own right as well as impediments to the best treatment of various conditions, including infectious, autoimmune, and neoplastic maladies. Rapid drug Desensitization (RDD) is an effective mechanism for safely administering important medications while minimizing or entirely circumventing such adverse reactions in sensitized patients. We reviewed the literature on RDD in the last 10 years, including our experience from the Brigham and Women’s Hospital Desensitization Program with hundreds of patients desensitized to a broad variety of drugs. RDD in our programme has been uniformly successful in patients with hypersensitivity reactions to antibiotics, chemotherapeutics, and monoclonal antibodies. Any reactions that occur during Desensitization are generally much less severe than the initial hypersensitivity reaction to the drug, and patients have received the full dose of the desired medication 99.9% of the time out of (796) Desensitizations. To date, there have been no fatalities. RDD is a safe and highly effective method for treating sensitized patients with the optimal pharmacologic agents. Its use should be expanded, but because patient safety is paramount, protocols must be created, reviewed, and overseen by allergist–immunologists with special training and experience in modern techniques of Desensitization.
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hypersensitivity reactions to mabs 105 Desensitizations in 23 patients from evaluation to treatment
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Patrick J Brennan, Tito Rodriguez Bouza, Ida F Hsu, David E Sloane, Mariana CastellsAbstract:Background: Rapid Desensitization, a procedure for graded drug administration, allows for the safe readministration of a medication after certain types of hypersensitivity reactions (HSRs) and is indicated in cases in which there are no reasonable therapeutic alternatives. The use of rapid Desensitization for HSRs to mAbs has not been validated. Objective: We sought to describe our experience with rapid Desensitization to mAbs, including rituximab, infliximab, and trastuzumab. Methods: One hundred five rapid Desensitizations were performed in 23 patients with a standardized 12-step, 6-hour protocol. Our approach to patient evaluation before Desensitization is described. The severity, characteristics, and timing of both initial HSRs and HSRs during Desensitization were determined by means of retrospective review of medical records. After a reaction during Desensitization, patient-specific protocol modifications were made before each subsequent Desensitization. Results: 104 of 105 Desensitizations undertaken were successfully completed. We observed HSRs during 29% of Desensitizations, including 27 mild reactions, 1 moderate reaction, and 2 severe reactions. Overall, reactions during Desensitization were markedly less severe than initial HSRs, but reactions did recur in a minority of successive Desensitizations. Conclusions: Rapid Desensitization is a promising method for the delivery of monoclonal therapeutics after an HSR, but the possibility of a reaction remains with each Desensitization. (J Allergy Clin Immunol 2009;124:1259-66.)
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rapid Desensitization for hypersensitivity reactions to medications
Immunology and Allergy Clinics of North America, 2009Co-Authors: Mariana CastellsAbstract:Drug Desensitization is the induction of temporary clinical unresponsiveness to drug antigens to which patients have presented severe hypersensitivity reactions. It is typically achieved by gradual reintroduction of small doses of drug antigens at fixed time intervals, and it is aimed at providing increased safety and protection from side effects, including anaphylaxis. Delivery of full therapeutic doses is achieved during Desensitization, allowing patients to receive firstline chemotherapy, antibiotics, or monoclonal antibodies, as well as other drugs such as insulin, aspirin, and iron. Desensitizations are high-risk interventions. Inhibition of cellular activation mechanisms occurs during drug Desensitization, allowing for the protective clinical outcomes and lack of side effects in the majority of cases, but the cellular and molecular inhibitory mechanisms are incompletely understood. The indication for Desensitization protocols can only be done by trained allergists and immunologists and should be implemented as standard of care because of their high success rates and outcomes-demonstrated safety profile.
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hypersensitivity reactions to chemotherapy outcomes and safety of rapid Desensitization in 413 cases
The Journal of Allergy and Clinical Immunology, 2008Co-Authors: Mariana Castells, Ida F Hsu, David E Sloane, Nichole M Tennant, Nora A Barrett, David I Hong, Tanya M Laidlaw, Henry J Legere, Samridhi N Nallamshetty, Ross I PalisAbstract:Background Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. Objective We have developed a standardized rapid Desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. Methods Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid Desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial Desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. Results Of the 413 Desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first Desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. Conclusions Our standardized 12-step protocol for rapid drug Desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.
Robert J Lefkowitz - One of the best experts on this subject based on the ideXlab platform.
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adenovirus mediated genetic manipulation of the myocardial s adrenergic signaling system in transplanted hearts
The Journal of Thoracic and Cardiovascular Surgery, 2000Co-Authors: Ashish S Shah, Robert J Lefkowitz, David C White, Oliver Tai, Jonathan A Hata, Katrina Wilson, Anne M Pippen, Alan P Kypson, Donald D Glower, Walter J KochAbstract:Abstract Objectives: Ex vivo perfusion of the cardiac allograft during organ procurement is an ideal environment for adenoviral vectors with transgenes that target improving graft contractility. One such target is the β-adrenergic receptor–signaling system, in which alterations in transgenic mice have elucidated novel means to improve the function of the heart in vivo. The purpose of the current study was to determine the functional consequences of β-adrenergic receptor manipulation in a rabbit model of cardiac allograft transplantation. Methods: New Zealand White rabbits weighing 3 kg served as recipients to 1-kg outbred donors. Donor hearts were arrested and harvested, and 1 of 3 adenoviral constructs was administered into the aortic root perfusing the graft. Transgenes delivered encoded either the human β 2 -adrenergic receptor, a peptide inhibitor of β-adrenergic receptor densensitization, or the marker transgene β-galactosidase. Results: Five days after cervical heterotopic transplantation, left ventricular performance was measured on a Langendorff apparatus. A moderate pattern of rejection was seen in all grafts. Biventricular myocyte expression of β-galactosidase was observed, and β 2 -adrenergic receptor density was elevated 10-fold in grafts that received adeno-β 2 -adrenergic receptor. Left ventricular systolic and diastolic performance was significantly increased in grafts transfected with either adeno-β 2 -adrenergic receptor or adeno-β-adrenergic receptor densensitization compared with control grafts that received adeno-β-galactosidase. Conclusions: Ex vivo adenovirus-mediated gene transfer is feasible in a rabbit allograft model and, more important, genetic manipulation of β-adrenergic receptor signaling either by increasing β 2 -adrenergic receptor density or blocking endogenous receptor Desensitization improves graft function acutely in this allograft model. (J Thorac Cardiovasc Surg 2000;120:581-8)
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src mediated tyrosine phosphorylation of dynamin is required for beta2 adrenergic receptor internalization and mitogen activated protein kinase signaling
Journal of Biological Chemistry, 1999Co-Authors: Seungkirl Ahn, Robert J Lefkowitz, Stuart Maudsley, Louis M Luttrell, Yehia DaakaAbstract:Some forms of G protein-coupled receptor signaling, such as activation of mitogen-activated protein kinase cascade as well as resensitization of receptors after hormone-induced Desensitization, require receptor internalization via dynamin-dependent clathrin-coated pit mechanisms. Here we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites. Mutation of these residues to phenylalanine dramatically decreases the c-Src-mediated phosphorylation of dynamin following beta2-AR stimulation. Moreover, expression of Y231F/Y597F dynamin inhibits beta2-AR internalization and the isoproterenol-stimulated mitogen-activated protein kinase activation. Thus, agonist-induced, c-Src-mediated tyrosine phosphorylation of dynamin is essential for its function in clathrin mediated G protein-coupled receptor endocytosis.
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clathrin mediated endocytosis of the beta adrenergic receptor is regulated by phosphorylation dephosphorylation of beta arrestin1
Journal of Biological Chemistry, 1997Co-Authors: Fangtsyr Lin, Kathleen M Krueger, Yehia Daaka, Julie A Pitcher, Humphrey E Kendall, Zoey L Fredericks, Robert J LefkowitzAbstract:β-Arrestins serve a dual regulatory role in the life cycle of G protein-coupled receptors such as the β2-adrenergic receptor. First, they mediate rapid Desensitization by binding to G protein-coupled receptor kinase-phosphorylated receptors. Second, they target the receptors for internalization into endosomal vesicles, wherein receptor dephosphorylation and resensitization occur. Here we report that phosphorylation of a carboxyl-terminal serine (Ser-412) in β-arrestin1 regulates its endocytotic but not its Desensitization function. Cytoplasmic β-arrestin1 is constitutively phosphorylated and is recruited to the plasma membrane by agonist stimulation of the receptors. At the plasma membrane, β-arrestin1 is rapidly dephosphorylated, a process that is required for its clathrin binding and receptor endocytosis but not for its receptor binding and Desensitization. Once internalized, β-arrestin1 is rephosphorylated. Thus, as with the classical endocytic adaptor protein complex AP2, β-arrestin1 functions as a clathrin adaptor in receptor endocytosis which is regulated by dephosphorylation at the plasma membrane.
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the role of sequestration in g protein coupled receptor resensitization regulation of β2 adrenergic receptor dephosphorylation by vesicular acidification
Journal of Biological Chemistry, 1997Co-Authors: Kathleen M Krueger, Yehia Daaka, Julie A Pitcher, Robert J LefkowitzAbstract:G protein-coupled receptor kinases phosphorylate the agonist occupied conformation of G protein-coupled receptors in the plasma membrane, leading to their Desensitization. Receptor resensitization requires receptor dephosphorylation, a process which is mediated by a plasma and vesicular membrane-associated form of PP-2A. We present evidence that, like receptor phosphorylation, receptor dephosphorylation is tightly regulated, requiring a specific receptor conformation induced by vesicular acidification. In vitro, spontaneous dephosphorylation of phosphorylated receptors is observed only at acidic pH. Furthermore, in intact cells upon agonist stimulation, phosphorylated receptors traffic from the plasma membrane to vesicles where they become physically associated with the phosphatase and dephosphorylated. Treatment of cells with NH4Cl, which disrupts the acidic pH found in endosomal vesicles, blocks association of the receptors with the phosphatase and blocks receptor dephosphorylation. These findings suggest that a conformational change in the receptor induced by acidification of the endosomal vesicles is the key determinant regulating receptor dephosphorylation and resensitization.
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mechanisms of beta adrenergic receptor Desensitization and resensitization
Advances in pharmacology, 1997Co-Authors: Robert J Lefkowitz, Kathleen M Krueger, Julie A Pitcher, Yehia DaakaAbstract:Publisher Summary Desensitization represents the summation of several different processes, including receptor phosphorylation, receptor sequestration (defined as the agonist-induced translocation of receptor away from the plasma membrane), enhanced degradation of intracellular messengers, and degradation of receptor protein. Rapid receptor Desensitization, however, appears to be mediated by uncoupling of the receptor from its respective G protein, a consequence of receptor phosphorylation. In the case of the β 2 -adrenergic receptor ( β 2 AR), phosphorylation by two distinct classes of serine-threonine kinases leads to receptor Desensitization. The first class, the second-messenger—dependent kinases—cyclic adenosine monophosphate (CAMP)-dependent protein kinase (PKA) and protein kinase C—phosphorylate and directly uncouple β 2 AR from G s . Because these kinases phosphorylate receptors in an agonist-independent manner, this process permits cross-talk between receptor families. The second class of enzymes, the G protein-coupled receptor kinases (GRKs), plays a highly specialized role in receptor Desensitization because only agonist-occupied receptors serve as substrates for these enzymes. In the case of GRKs, the very signal that promotes activation of the G protein and the effector (that is, ligand binding) also promotes the Desensitization of that specific receptor. Once uncoupled from the G protein, receptor function can be restored only by receptor dephosphorylation, a process termed resensitization . The phosphatases and regulatory mechanisms involved in this resensitization process have only recently begun to be elucidated and are included in this chapter.
Johnson T Wong - One of the best experts on this subject based on the ideXlab platform.
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rituximab hypersensitivity evaluation Desensitization and potential mechanisms
The Journal of Allergy and Clinical Immunology: In Practice, 2017Co-Authors: Johnson T Wong, Aidan A LongAbstract:Background Rituximab (Rituxan) hypersensitivity (RITS) can be severe and limits the ability to further administer the treatment. Understanding its pattern and Desensitization may permit administration in difficult cases. Objective Analyze RITS patient characteristics, hypersensitivity pattern, and Desensitization outcomes to optimize management. Methods Twenty-five patients with RITS were referred to the Allergy/Immunology Unit at Massachusetts General Hospital over 5 1/2 years. Their clinical reaction patterns were analyzed. Drug Desensitizations were performed using 3 related continuous intravenous protocols that were chosen on the basis of clinical history, skin test reactivity, and the patient's previous Desensitization outcomes. Results Of the 25 referred patients, 23 had lymphoma of various types. The 25 patients underwent 170 continuous intravenous Desensitizations based on 3 related protocols, with most based on the intermediate protocol. All but 2 Desensitizations were completed successfully. Overall 24% of the Desensitizations were complicated by hypersensitivity reactions. Two patients with serum sickness and a patient with mast cell disorder were also successfully managed. The average hypersensitivity reaction grade was 3.0 (2-4) before Desensitization and 0.41 with Desensitization. Skin tests were performed in 18 patients, with 5 patients positive initially and 2 more converted from negative to positive. Skin test status was not helpful for risk stratification for hypersensitivity reactions. Tryptase level was elevated during 21% of Desensitizations with reactions but rare among asymptomatic Desensitizations. Conclusions Nearly all patients with severe sensitivity to rituximab can be successfully desensitized. IgE-mediated mechanism and mast cell degranulation, in addition to cytokine release syndrome and tumor lysis syndrome, may contribute to a significant portion of hypersensitivity reactions among patients with RITS.
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oxaliplatin hypersensitivity evaluation implications of skin testing and Desensitization
The Journal of Allergy and Clinical Immunology: In Practice, 2014Co-Authors: Johnson T Wong, Aleena Banerji, Morris Ling, Sarita U Patil, Aidan A LongAbstract:Background Oxaliplatin hypersensitivity (OXS) presents a challenge in the treatment of oxaliplatin-sensitive malignancies. Objective To analyze patient characteristics of patients with OXS, skin test results, and Desensitization outcomes to optimize management. Methods Over 5 years, 48 patients with OXS were referred to the allergy/immunology unit at Massachusetts General Hospital. Their clinical reaction patterns were analyzed. Immediate hypersensitivity skin testing was used for risk stratification, and drug Desensitizations were performed by using 3 related continuous intravenous protocols that were chosen based on clinical history, skin test reactivity, and the patients' previous Desensitization outcomes. Results OXS occurred in both sexes, with mostly gastrointestinal-related tumors. Hypersensitivity reaction (HSR) onset had occurred during any course of therapy (course nos. 1-28), with a median onset at course no. 8. HSR to oxaliplatin was similar to those observed with cisplatin and carboplatin, including cutaneous, cardiovascular, pulmonary, and gastrointestinal symptoms. However, neurologic symptoms, including tingling, and systemic symptoms, including fever and chills, occurred more often in patients with OXS. Unique to OXS, 2 patients developed drug-induced thrombocytopenia; 1 patients also developed drug-induced hemolytic anemia. Skin testing was positive for the majority of patients with OXS (27/46 [59%]) and correlated with a greater likelihood of developing an HSR during subsequent Desensitizations. We safely performed 200 Desensitizations in 48 patients with OXS. Conclusion OXS is common with much similarity to other platin agents but also have distinct differences in the onset of hypersensitivity, sex, tumor type, drug-induced hemolytic anemia, and drug-induced thrombocytopenia. Skin testing was helpful for risk stratification. All of the Desensitizations were completed successfully.
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risk stratification for Desensitization of patients with carboplatin hypersensitivity clinical presentation and management
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Paul E Hesterberg, Aleena Banerji, Eyal Oren, Richard T Penson, C N Krasner, Michael V Seiden, Johnson T WongAbstract:Background Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for Desensitization is uncertain. Objectives To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin Desensitization. Methods Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 Desensitizations to carboplatin. Results Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR ( 9 months) tested positive ( P + and 11 ST − patients underwent Desensitization to carboplatin. Seven ST + patients (37%) had mild HSR during Desensitization but completed the Desensitization with additional treatment or protocol modification. ST − patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST – with repeated testing. Six of 8 ST − patients (75%) with remote HSR reacted during Desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST + before the second Desensitization. Carboplatin Desensitization was successfully completed in 105 of 106 (99%) treatment courses. Conclusions The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent Desensitization. Initial ST − patients with a remote history of HSR are at high risk for conversion to ST + and can develop more severe HSR.
Aleena Banerji - One of the best experts on this subject based on the ideXlab platform.
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risk stratification protocol for carboplatin and oxaliplatin hypersensitivity repeat skin testing to identify drug allergy
Annals of Allergy Asthma & Immunology, 2015Co-Authors: Alberta L Wang, Aidan A Long, Sarita U Patil, Aleena BanerjiAbstract:Abstract Background Hypersensitivity reactions (HSRs) to platinum-based chemotherapies are increasingly being recognized. The authors developed a novel risk-stratification protocol that was used successfully in a small number of patients with carboplatin-induced HSRs. Objective To describe the utility of this protocol in a large number of patients with carboplatin- or oxaliplatin-induced HSRs. Methods A 5-year retrospective review of patients referred to Massachusetts General Hospital with carboplatin- or oxaliplatin-induced HSR was performed. Patients were managed using a risk-stratification protocol using 3 repeat skin tests (STs) with intervening Desensitizations. If the repeat ST result remained negative 3 times, patients received subsequent infusions without Desensitization. Results From 2008 to 2012, 142 patients (92 treated with carboplatin, 50 treated with oxaliplatin) completed 574 Desensitizations. Most patients were women (84.5%, mean ± SD 58.1 ± 9.3 years). Patients with carboplatin-induced HSRs were classified as having positive (n = 32, 34.8%), negative (n = 38, 41.3%), or converted (n = 22, 23.9%) ST reactions when the initial negative ST reaction converted to positive at repeat ST. Of those with oxaliplatin-induced HSRs, 22 (44%) had positive, 25 (50%) had negative, and 3 (6%) had converted ST reactions. Of the patients with negative ST reactions, 17 with carboplatin-induced HSRs and 16 with oxaliplatin-induced HSRs safely completed 59 and 95 outpatient infusions, respectively, without Desensitizations. For carboplatin and oxaliplatin, ST conversion was associated with an interval of at least 6 months from the HSR to the initial ST (carboplatin, P = .002; oxaliplatin, P = .045). Conclusion This risk-stratification protocol for presumed carboplatin- and oxaliplatin-induced HSRs safely identifies false-negative ST reactions and nonallergic patients who can receive infusions without Desensitizations. This leads to fewer unnecessary Desensitizations and improved patient care.
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oxaliplatin hypersensitivity evaluation implications of skin testing and Desensitization
The Journal of Allergy and Clinical Immunology: In Practice, 2014Co-Authors: Johnson T Wong, Aleena Banerji, Morris Ling, Sarita U Patil, Aidan A LongAbstract:Background Oxaliplatin hypersensitivity (OXS) presents a challenge in the treatment of oxaliplatin-sensitive malignancies. Objective To analyze patient characteristics of patients with OXS, skin test results, and Desensitization outcomes to optimize management. Methods Over 5 years, 48 patients with OXS were referred to the allergy/immunology unit at Massachusetts General Hospital. Their clinical reaction patterns were analyzed. Immediate hypersensitivity skin testing was used for risk stratification, and drug Desensitizations were performed by using 3 related continuous intravenous protocols that were chosen based on clinical history, skin test reactivity, and the patients' previous Desensitization outcomes. Results OXS occurred in both sexes, with mostly gastrointestinal-related tumors. Hypersensitivity reaction (HSR) onset had occurred during any course of therapy (course nos. 1-28), with a median onset at course no. 8. HSR to oxaliplatin was similar to those observed with cisplatin and carboplatin, including cutaneous, cardiovascular, pulmonary, and gastrointestinal symptoms. However, neurologic symptoms, including tingling, and systemic symptoms, including fever and chills, occurred more often in patients with OXS. Unique to OXS, 2 patients developed drug-induced thrombocytopenia; 1 patients also developed drug-induced hemolytic anemia. Skin testing was positive for the majority of patients with OXS (27/46 [59%]) and correlated with a greater likelihood of developing an HSR during subsequent Desensitizations. We safely performed 200 Desensitizations in 48 patients with OXS. Conclusion OXS is common with much similarity to other platin agents but also have distinct differences in the onset of hypersensitivity, sex, tumor type, drug-induced hemolytic anemia, and drug-induced thrombocytopenia. Skin testing was helpful for risk stratification. All of the Desensitizations were completed successfully.
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risk stratification for Desensitization of patients with carboplatin hypersensitivity clinical presentation and management
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Paul E Hesterberg, Aleena Banerji, Eyal Oren, Richard T Penson, C N Krasner, Michael V Seiden, Johnson T WongAbstract:Background Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for Desensitization is uncertain. Objectives To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin Desensitization. Methods Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 Desensitizations to carboplatin. Results Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR ( 9 months) tested positive ( P + and 11 ST − patients underwent Desensitization to carboplatin. Seven ST + patients (37%) had mild HSR during Desensitization but completed the Desensitization with additional treatment or protocol modification. ST − patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST – with repeated testing. Six of 8 ST − patients (75%) with remote HSR reacted during Desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST + before the second Desensitization. Carboplatin Desensitization was successfully completed in 105 of 106 (99%) treatment courses. Conclusions The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent Desensitization. Initial ST − patients with a remote history of HSR are at high risk for conversion to ST + and can develop more severe HSR.
Marc G Caron - One of the best experts on this subject based on the ideXlab platform.
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association of beta arrestin with g protein coupled receptors during clathrin mediated endocytosis dictates the profile of receptor resensitization
Journal of Biological Chemistry, 1999Co-Authors: Robert H Oakley, Larry S Barak, Stephane A Laporte, Jason A Holt, Marc G CaronAbstract:Resensitization of G protein-coupled receptors (GPCRs) following agonist-mediated Desensitization is a necessary step for maintaining physiological responsiveness. However, the molecular mechanisms governing the nature of GPCR resensitization are poorly understood. Here, we examine the role of beta-arrestin in the resensitization of the beta(2) adrenergic receptor (beta(2)AR), known to recycle and resensitize rapidly, and the vasopressin V2 receptor (V2R), known to recycle and resensitize slowly. Upon agonist activation, both receptors recruit beta-arrestin to the plasma membrane and internalize in a beta-arrestin- and clathrin-dependent manner. However, whereas beta-arrestin dissociates from the beta(2)AR at the plasma membrane, it internalizes with the V2R into endosomes. The differential trafficking of beta-arrestin and the ability of these two receptors to dephosphorylate, recycle, and resensitize is completely reversed when the carboxyl-terminal tails of these two receptors are switched. Moreover, the ability of beta-arrestin to remain associated with desensitized GPCRs during clathrin-mediated endocytosis is mediated by a specific cluster of phosphorylated serine residues in the receptor carboxyl-terminal tail. These results demonstrate that the interaction of beta-arrestin with a specific motif in the GPCR carboxyl-terminal tail dictates the rate of receptor dephosphorylation, recycling, and resensitization, and thus provide direct evidence for a novel mechanism by which beta-arrestins regulate the reestablishment of GPCR responsiveness.
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association of beta arrestin with g protein coupled receptors during clathrin mediated endocytosis dictates the profile of receptor resensitization
Journal of Biological Chemistry, 1999Co-Authors: Robert H Oakley, Larry S Barak, Stephane A Laporte, Jason A Holt, Marc G CaronAbstract:Abstract Resensitization of G protein-coupled receptors (GPCRs) following agonist-mediated Desensitization is a necessary step for maintaining physiological responsiveness. However, the molecular mechanisms governing the nature of GPCR resensitization are poorly understood. Here, we examine the role of β-arrestin in the resensitization of the β2 adrenergic receptor (β2AR), known to recycle and resensitize rapidly, and the vasopressin V2 receptor (V2R), known to recycle and resensitize slowly. Upon agonist activation, both receptors recruit β-arrestin to the plasma membrane and internalize in a β-arrestin- and clathrin-dependent manner. However, whereas β-arrestin dissociates from the β2AR at the plasma membrane, it internalizes with the V2R into endosomes. The differential trafficking of β-arrestin and the ability of these two receptors to dephosphorylate, recycle, and resensitize is completely reversed when the carboxyl-terminal tails of these two receptors are switched. Moreover, the ability of β-arrestin to remain associated with desensitized GPCRs during clathrin-mediated endocytosis is mediated by a specific cluster of phosphorylated serine residues in the receptor carboxyl-terminal tail. These results demonstrate that the interaction of β-arrestin with a specific motif in the GPCR carboxyl-terminal tail dictates the rate of receptor dephosphorylation, recycling, and resensitization, and thus provide direct evidence for a novel mechanism by which β-arrestins regulate the reestablishment of GPCR responsiveness.
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a central role for beta arrestins and clathrin coated vesicle mediated endocytosis in beta2 adrenergic receptor resensitization differential regulation of receptor resensitization in two distinct cell types
Journal of Biological Chemistry, 1997Co-Authors: Jie Zhang, Larry S Barak, Marc G Caron, Katharine E Winkler, Stephen S G FergusonAbstract:G protein-coupled receptor (GPCR) sequestration to endosomes is proposed to be the mechanism by which G protein-coupled receptor kinase (GRK)-phosphorylated receptors are dephosphorylated and resensitized. The identification of beta-arrestins as GPCR trafficking molecules suggested that beta-arrestins might represent critical determinants for GPCR resensitization. Therefore, we tested whether beta2-adrenergic receptor (beta2AR) resensitization was dependent upon beta-arrestins and an intact clathrin-coated vesicle endocytic pathway. The overexpression of either the beta-arrestin 1-V53D dominant negative inhibitor of beta2AR sequestration or dynamin I-K44A to block clathrin-coated vesicle-mediated endocytosis impaired both beta2AR dephosphorylation and resensitization. In contrast, resensitization of a sequestration-impaired beta2AR mutant (Y326A) was reestablished following the overexpression of either GRK2 or beta-arrestin 1. Moreover, beta2ARs did not resensitize in COS-7 cells as the consequence of impaired sequestration and dephosphorylation. However, beta2AR resensitization was restored in these cells following the overexpression of beta-arrestin 2. These findings demonstrate, using both loss and gain of function paradigms, that beta2AR dephosphorylation and resensitization are dependent upon an intact sequestration pathway. These studies also indicate that beta-arrestins play an integral role in regulating not only the Desensitization and intracellular trafficking of GPCRs but their ability to resensitize. beta-Arrestin expression levels appear to underlie cell type-specific differences in the regulation of GPCR resensitization.
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g protein coupled receptor regulation role of g protein coupled receptor kinases and arrestins
Canadian Journal of Physiology and Pharmacology, 1996Co-Authors: Stephen S G Ferguson, Larry S Barak, J Zhang, Marc G CaronAbstract:G-protein-coupled receptors (GPCRs) represent a large family of proteins that transduce extracellular signals to the interior of cells. Signalling through these receptors rapidly desensitized primarily as the consequence of receptor phosphorylation, but receptor sequestration and downregulation can also contribute to this process. Two families of serine/threonine kinases, second messenger dependent protein kinases and receptor-specific G-protein-coupled receptor kinases (GRKs), phosphorylate GPCRs and thereby contribute to receptor Desensitization. Receptor-specific phosphorylation of GPCRs promotes the binding of cytosolic proteins referred to as arrestins, which function to further uncouple GPCRs from their heterotrimeric G-proteins. To date, the GRK protein family consists of six members, which can be further classified into subgroups according to sequence homology and functional similarities. The arrestin protein family also comprises six members, which are subgrouped on the basis of sequence homology and tissue distribution. While the molecular mechanisms contributing to GPCR Desensitization are fairly well characterized, little is known about the mechanism(s) by which GPCR responsiveness is reestablished, other than that receptor sequestration (internalization) might be involved. The goal of the present review is to overview current understanding of the regulation of GPCR responsiveness. In particular, we will review new evidence suggesting a pleiotropic role for GRKs and arrestins in the regulation of GPCR responsiveness. GRK-mediated phosphorylation and arrestin binding are not only involved in the functional uncoupling of GPCRs but they are also intimately involved in promoting GPCR sequestration and as such likely play an important role in mediating the subsequent resensitization of GPCRs.
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role of β arrestin in mediating agonist promoted g protein coupled receptor internalization
Science, 1996Co-Authors: Stephen S G Ferguson, Larry S Barak, William E Downey, Annemarie Colapietro, Luc Menard, Marc G CaronAbstract:β-Arrestins are proteins that bind phosphorylated heterotrimeric GTP-binding protein (G protein)-coupled receptors (GPCRs) and contribute to the Desensitization of GPCRs by uncoupling the signal transduction process. Resensitization of GPCR responsiveness involves agonist-mediated receptor sequestration. Overexpression of β-arrestins in human embryonic kidney cells rescued the sequestration of β 2 -adrenergic receptor (β 2 AR) mutants defective in their ability to sequester, an effect enhanced by simultaneous overexpression of β-adrenergic receptor kinase 1. Wild-type β 2 AR sequestration was inhibited by the overexpression of two β-arrestin mutants. These findings suggest that β-arrestins play an integral role in GPCR internalization and thus serve a dual role in the regulation of GPCR function.
