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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Drug reaction with eosinophilia and systemic symptoms &#40;DRESS&#41; syndrome is a rare and severe adverse drug reaction&#44; occurring generally about two to eight weeks after the introduction of a causative drug&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Cutaneous involvement usually begins with a morbilliform eruption&#44; with cutaneous edema&#44; mainly involving the face&#44; upper trunk&#44; and extremities&#44; spreading from the face to the entire body&#44; with edema of the face being a characteristic finding&#46; Other cutaneous manifestations include vesicles&#44; pustules&#44; erythroderma&#44; and purpuric lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> DRESS syndrome can be accompanied by different systemic symptoms including fever&#44; lymphadenopathy&#44; hematological abnormalities&#44; or visceral involvement &#40;kidney&#44; liver&#44; heart&#44; lung&#44; muscle&#44; and even brain&#41;&#46; Blood test abnormalities typically persist for several days&#46; DRESS syndrome can be life-threatening and is associated with organ failure&#44; with a described mortality up to 10&#37;&#44; although analysis of prospective data shows a lower mortality rate&#44; around 2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Besides causative drug discontinuation&#44; supportive therapy is generally sufficient and may include antipyretic drugs&#44; systemic antihistamines&#44; and topic corticosteroids&#46; However&#44; in severe cases&#44; with visceral involvement&#44; systemic corticosteroids &#40;0&#46;5&#8211;2&#46;0&#8239;mg&#47;kg&#41; are usually needed&#46; Aromatic anticonvulsants &#40;e&#46;g&#46; phenytoin&#44; carbamazepine&#44; phenobarbital&#41; and sulfonamides are the most frequent drugs associated with DRESS syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The authors describe a DRESS syndrome induced by osimertinib&#44; in an advanced EGFR mutated lung cancer patient&#46; This third-generation agent was initially associated with scarce skin toxicity in clinical trials&#44; compared to standard agents&#46; After FLAURA trial results showing higher efficacy of osimertinib compared to standard EGFR-tyrosine kinase inhibitors&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> osimertinib became the first-line treatment of EGFR mutation-positive advanced NSCLC&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> enhancing the number of patients potentially treated with this agent&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A sixty-year-old woman was initially admitted to the hospital with seizures&#46; The brain scan showed intracranial space-occupying lesions&#46; She started levetiracetam at the end of December 2018 and carbamazepine in January 2019&#46; Investigation revealed a stage IV EGFR mutated &#40;deletion on exon 19&#41; lung adenocarcinoma with the involvement of the central nervous system&#46; She was submitted to radiosurgery and she started systemic therapy with osimertinib &#40;80&#8239;mg daily&#41;&#44; in early March&#46; After eight days&#44; she was admitted to the hospital with a painful and itchy generalized skin rash on face&#44; neck&#44; trunk&#44; and lower limbs&#44; with preserved skin integrity and with no systemic symptoms&#46; Osimertinib induced skin toxicity was assumed and the drug was stopped&#46; She was discharged from the hospital with topic steroid therapy&#46; But&#44; three weeks after osimertinib suspension&#44; she was readmitted to the hospital with widespread erythema&#44; impaired skin integrity&#44; with no mucosal involvement&#44; and accompanied by fever &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Blood tests revealed eosinophilia &#40;1240&#47;&#956;l&#59; 12&#46;7&#37;&#41; with no leukocytosis&#44; acute kidney failure &#40;AKIN II&#41; with ionic changes&#44; and elevation of alkaline phosphatase and lactate dehydrogenase&#44; suggesting DRESS syndrome&#46; She started systemic corticoid therapy &#40;methylprednisolone 1&#8239;mg&#47;kg day&#41;&#44; teicoplanin&#44; and fluid therapy&#44; with clinical improvement&#46; As skin involvement had worsened after osimertinib suspension&#44; it was thought it could be related to carbamazepine&#44; which was permanently suspended&#46; Thus&#44; after two weeks&#44; with clinical improvement&#44; and under systemic corticoid de-escalation&#44; osimertinib was reintroduced with no evident adverse reaction&#46; The patient remained hospitalized for two more weeks for surveillance&#46; But&#44; eighteen days after osimertinib reintroduction&#44; she was readmitted to the hospital with a severe generalized rash all over the body with epidermal detachment and erosions greater than 30&#37; of body surface area and no mucosal involvement&#46; At that time&#44; her blood tests revealed again a slight eosinophilia &#40;660&#47;&#956;l&#59; 7&#46;3&#37;&#41; with no leukocytosis and acute kidney failure &#40;AKIN II&#41;&#46; Osimertinib was stopped again and systemic corticoid was escalated to prednisolone 40&#8239;mg daily&#46; Skin biopsy was compatible with DRESS syndrome&#44; showing a superficial dermal lymphocytic infiltrate&#44; with similar counts of CD4&#43; and CD8&#43; cells &#40;some granzyme B positive&#41; and no eosinophils &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">In September 2019&#44; after de-escalating systemic corticoid and with the resolution of skin lesions and normalized kidney function&#44; she started gefitinib in the second line&#44; with no skin toxicity&#46; Unfortunately&#44; gefitinib was suspended in early November due to disease progression&#44; and the patient was kept under palliative care till the end of life&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The introduction of a new target agent in real-world clinical practice is always challenging as new toxicities may arise as the number of patients treated increases&#46; The particularity of our case is that this skin toxicity was induced by a novel drug&#44; initially reported as less associated with skin toxicity&#46; Further&#44; skin involvement had worsened after osimertinib suspension and the patient was under carbamazepine&#44; a frequently DRESS syndrome associated drug&#44; which made it difficult to associate osimertinib to this clinical situation&#46; It is important to notice that skin toxicity can prevail after discontinuation of a target agent&#46; To the best of our knowledge&#44; this is the first case of DRESS syndrome induced by osimertinib described in literature till now&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0025" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Letter to the Editor
Drug reaction with eosinophilia and systemic symptoms syndrome associated with osimertinib
S.C. Ferreiraa,
Corresponding author
sofiacferreira@gmail.com
asferreira@ipolisboa.min-saude.pt

Correspondent author at: Serviço de Oncologia Médica – Pavilhão de Medicina, 2º piso, Instituto Português de Oncologia de Lisboa Francisco Gentil, R. Prof. Lima Basto, 1099-023 Lisboa, Portugal.
, C. Gasparb, J. Dionísiob, C. Mourac, T. Almodovarb
a Serviço de Oncologia Médica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
b Serviço de Pneumologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
c Serviço de Dermatologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal
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hematological abnormalities&#44; or visceral involvement &#40;kidney&#44; liver&#44; heart&#44; lung&#44; muscle&#44; and even brain&#41;&#46; Blood test abnormalities typically persist for several days&#46; DRESS syndrome can be life-threatening and is associated with organ failure&#44; with a described mortality up to 10&#37;&#44; although analysis of prospective data shows a lower mortality rate&#44; around 2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Besides causative drug discontinuation&#44; supportive therapy is generally sufficient and may include antipyretic drugs&#44; systemic antihistamines&#44; and topic corticosteroids&#46; However&#44; in severe cases&#44; with visceral involvement&#44; systemic corticosteroids &#40;0&#46;5&#8211;2&#46;0&#8239;mg&#47;kg&#41; are usually needed&#46; Aromatic anticonvulsants &#40;e&#46;g&#46; phenytoin&#44; carbamazepine&#44; phenobarbital&#41; and sulfonamides are the most frequent drugs associated with DRESS syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The authors describe a DRESS syndrome induced by osimertinib&#44; in an advanced EGFR mutated lung cancer patient&#46; This third-generation agent was initially associated with scarce skin toxicity in clinical trials&#44; compared to standard agents&#46; After FLAURA trial results showing higher efficacy of osimertinib compared to standard EGFR-tyrosine kinase inhibitors&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> osimertinib became the first-line treatment of EGFR mutation-positive advanced NSCLC&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> enhancing the number of patients potentially treated with this agent&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">A sixty-year-old woman was initially admitted to the hospital with seizures&#46; The brain scan showed intracranial space-occupying lesions&#46; She started levetiracetam at the end of December 2018 and carbamazepine in January 2019&#46; Investigation revealed a stage IV EGFR mutated &#40;deletion on exon 19&#41; lung adenocarcinoma with the involvement of the central nervous system&#46; She was submitted to radiosurgery and she started systemic therapy with osimertinib &#40;80&#8239;mg daily&#41;&#44; in early March&#46; After eight days&#44; she was admitted to the hospital with a painful and itchy generalized skin rash on face&#44; neck&#44; trunk&#44; and lower limbs&#44; with preserved skin integrity and with no systemic symptoms&#46; Osimertinib induced skin toxicity was assumed and the drug was stopped&#46; She was discharged from the hospital with topic steroid therapy&#46; But&#44; three weeks after osimertinib suspension&#44; she was readmitted to the hospital with widespread erythema&#44; impaired skin integrity&#44; with no mucosal involvement&#44; and accompanied by fever &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Blood tests revealed eosinophilia &#40;1240&#47;&#956;l&#59; 12&#46;7&#37;&#41; with no leukocytosis&#44; acute kidney failure &#40;AKIN II&#41; with ionic changes&#44; and elevation of alkaline phosphatase and lactate dehydrogenase&#44; suggesting DRESS syndrome&#46; She started systemic corticoid therapy &#40;methylprednisolone 1&#8239;mg&#47;kg day&#41;&#44; teicoplanin&#44; and fluid therapy&#44; with clinical improvement&#46; As skin involvement had worsened after osimertinib suspension&#44; it was thought it could be related to carbamazepine&#44; which was permanently suspended&#46; Thus&#44; after two weeks&#44; with clinical improvement&#44; and under systemic corticoid de-escalation&#44; osimertinib was reintroduced with no evident adverse reaction&#46; The patient remained hospitalized for two more weeks for surveillance&#46; But&#44; eighteen days after osimertinib reintroduction&#44; she was readmitted to the hospital with a severe generalized rash all over the body with epidermal detachment and erosions greater than 30&#37; of body surface area and no mucosal involvement&#46; At that time&#44; her blood tests revealed again a slight eosinophilia &#40;660&#47;&#956;l&#59; 7&#46;3&#37;&#41; with no leukocytosis and acute kidney failure &#40;AKIN II&#41;&#46; Osimertinib was stopped again and systemic corticoid was escalated to prednisolone 40&#8239;mg daily&#46; Skin biopsy was compatible with DRESS syndrome&#44; showing a superficial dermal lymphocytic infiltrate&#44; with similar counts of CD4&#43; and CD8&#43; cells &#40;some granzyme B positive&#41; and no eosinophils &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">In September 2019&#44; after de-escalating systemic corticoid and with the resolution of skin lesions and normalized kidney function&#44; she started gefitinib in the second line&#44; with no skin toxicity&#46; Unfortunately&#44; gefitinib was suspended in early November due to disease progression&#44; and the patient was kept under palliative care till the end of life&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The introduction of a new target agent in real-world clinical practice is always challenging as new toxicities may arise as the number of patients treated increases&#46; The particularity of our case is that this skin toxicity was induced by a novel drug&#44; initially reported as less associated with skin toxicity&#46; Further&#44; skin involvement had worsened after osimertinib suspension and the patient was under carbamazepine&#44; a frequently DRESS syndrome associated drug&#44; which made it difficult to associate osimertinib to this clinical situation&#46; It is important to notice that skin toxicity can prevail after discontinuation of a target agent&#46; To the best of our knowledge&#44; this is the first case of DRESS syndrome induced by osimertinib described in literature till now&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0025" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Article information
ISSN: 25310437
Original language: English
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Pulmonology

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