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Original article
Hepatic immune-mediatedadverseeffects of immune checkpoint inhibitors: analysis of real-life experience
Joana Alves da Silvaa,
Corresponding author
joana.ines.silva@gmail.com

Corresponding author.
, Daniela Falcãoa, Cláudia Cardosob, Ana Luísa Piresb, António Araújob,c, Fernando Castro-Poçasa,b
a Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
b Abel Salazar Biomedical Sciences Institute - University of Porto, Portugal
c Oncology Service, Pathology Department, Centro Hospitalar Universitário do Porto, Porto, Portugal
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atezolizumab &#40;anti-PD-L1&#41;&#59; ipilimumab and tremelimumab &#40;anti-CTLA-4&#41;&#46;</p><p id="para0008" class="elsevierStylePara elsevierViewall">Immune-related adverse events &#40;irAE&#41; is the term for ICB&#39;s inflammatory side effects consequential to its increase in the activity of the immune system&#46; These irAE regularly involve the gastrointestinal tract&#44; endocrine glands&#44; skin and liver&#46; However&#44; they may affect any organ system <a class="elsevierStyleCrossRef" href="#bib0002">&#91;2&#93;</a>&#46; Immune-mediated liver injury &#40;IMLI&#41; has a reported incidence of 2&#8211;9&#37; in monotherapy&#44; and may be up to 18&#37; in patients treated with combination of anti-PD-1 and anti-CTLA-4 &#91;<a class="elsevierStyleCrossRef" href="#bib0003">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0004">4</a>&#93;&#46;</p><p id="para0009" class="elsevierStylePara elsevierViewall">The pathophysiology underlying irAE is unknown but is theorized that it relates to the role of immune checkpoints in immunologic homeostasis maintenance&#46; It is hypothesized that in addition to T-cell&#8211;mediated immunity&#44; anti&#8211;PD-1 or anti&#8211;PD-L1 treatment modulates humoral immunity&#44; enhancing pre-existing auto-antibodies <a class="elsevierStyleCrossRef" href="#bib0005">&#91;5&#93;</a>&#46; The extent to which autoantibodies &#40;rather than autoreactive T cells&#41; contribute to irAE remains unknown and may differ between different toxic effects&#46; Cytokines may also play a role on development of this adverse effects <a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a>&#46;</p><p id="para0010" class="elsevierStylePara elsevierViewall">IrAEs may warrant therapy&#39;s cessation or the administration of immunosuppressive agents <a class="elsevierStyleCrossRef" href="#bib0006">&#91;6&#93;</a>&#46; No prospective trials have defined strategies for effectively managing specific irAE&#46; Further clarification of irAE&#39;s characteristics is warranted&#44; considering the consequences of interrupting a potentially life-saving treatment and the adverse effects of long-term corticosteroids in high-doses&#46; In this study we perform a comprehensive clinical description of the hepatic irAEs associated with ICI in a Portuguese population of a tertiary centre hospital&#46;</p></span><span id="sec0002" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2</span><span class="elsevierStyleSectionTitle" id="cesectitle0011">Materials and methods</span><p id="para0011" class="elsevierStylePara elsevierViewall">This retrospective study was conducted at the Centro Hospitalar Universit&#225;rio do Porto with approval of the institution&#39;s Ethics Committee&#46;</p><span id="sec0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0012">Patients</span><p id="para0012" class="elsevierStylePara elsevierViewall">We included patients older than 18 years old&#44; who were &#40;1&#41; exposed to one or more ICIs between March 15<span class="elsevierStyleSup">th</span> of 2015 and December 15<span class="elsevierStyleSup">th</span> of 2019 that &#40;2&#41; were submitted at least to a one cycle of ICI in our hospital&#46; Nineteen patients were excluded due to lack of clinical information or loss of follow-up in this institution&#46;</p></span><span id="sec0004" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0013">Clinical information</span><p id="para0013" class="elsevierStylePara elsevierViewall">Clinical data was obtained retrospectively from the electronic medical records&#46;</p><p id="para0014" class="elsevierStylePara elsevierViewall">Data collected included demographic information &#40;age at the time of ICI initiation and sex&#41;&#59; smoke history&#59; comorbid illnesses &#40;based on the Charlson index&#41; <a class="elsevierStyleCrossRef" href="#bib0007">&#91;7&#93;</a>&#59; and presence of an auto-immune disease&#46; Alcohol use was not obtained because of the heterogeneity of its characterization according to each oncologist&#46; Clinical notes were also collected&#46;</p><p id="para0015" class="elsevierStylePara elsevierViewall">Oncologic information such as underlying cancer type and the presence of hepatic metastasis based on imagiological data&#44; was included&#46; The type&#44; and duration of ICI therapy&#44; as well as occurrence of nonhepatic irAEs&#44; were noted&#46;</p><p id="para0016" class="elsevierStylePara elsevierViewall">Biological data included aspartate aminotransferase &#40;AST&#44; normal range 10-30 U&#47;L for women and 10-34 U&#47;L&#41;&#44; alanine aminotransferase &#40;ALT&#44; normal range 10-36U&#47;L for women and 10-44 U&#47;L for men&#41;&#44; total bilirubin &#40;Bil-T&#44; normal range&#44; &#60;1mg&#47;dL&#41;&#44; alkaline phosphatase &#40;ALP&#44; normal range 35-104 U&#47;L for women and 40-129 U&#47;L for men&#41;&#44; gamma-glutamyltransferase &#40;GGT&#44; normal range 6-39U&#47;L for women and 10-66 U&#47;L for men&#41;&#46; Blood tests were performed per protocol before each immunotherapy injection&#46;</p></span><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0014">Liver injury definition</span><p id="para0017" class="elsevierStylePara elsevierViewall">Baseline liver biochemistries of serum AST&#44; ALT&#44; ALP and Bil-T were defined as those results obtained immediately prior to the first ICI dose&#46;</p><p id="para0018" class="elsevierStylePara elsevierViewall">Currently&#44; adverse events in oncology trials are often graded using the US National Cancer Institute Common Terminology Criteria for Adverse Events &#40;CTCAE&#41;&#46; These criteria grade adverse events &#40;including irAEs&#41; on a scale of 1&#8211;5&#44; denoting&#58; 1- mild reactions&#59; 2- moderate reactions&#59; 3- severe reactions&#59; 4- life-threatening events and 5- death <a class="elsevierStyleCrossRef" href="#bib0008">&#91;8&#93;</a>&#46;</p><p id="para0019" class="elsevierStylePara elsevierViewall">According to CTCAE version 4&#46;03 hepatoxicity is defined as grade 3 if&#58; &#40;1&#41; AST or ALT &#8805;5-20 times upper limit of normality &#40;x ULN&#41; and&#47;or &#40;2&#41; T-Bil&#62;3-10 x ULN&#59; and grade 4 if&#58; &#40;1&#41; AST or ALT &#62;20 x ULN and&#47;or &#40;2&#41; Bil-T &#62;10 x ULN&#46;</p><p id="para0020" class="elsevierStylePara elsevierViewall">According to Drug&#8208;Induced Liver Injury Network &#40;DILIN&#41; <a class="elsevierStyleCrossRef" href="#bib0009">&#91;9&#93;</a> study criteria&#44; drug-induced liver injury is defined as&#58; &#40;1&#41; serum ALT &#8805; 5x ULN&#59; and&#47;or &#40;2&#41; serum ALP &#8805; 2x ULN&#59; and&#47; or &#40;3&#41; Bil-T &#8805; 2&#46;5 mg&#47;dL &#40;or &#62; 2x baseline if baseline &#62; ULN&#41;&#46;</p><p id="para0021" class="elsevierStylePara elsevierViewall">In patients with abnormal liver tests prior to starting treatment with the implicated drug&#44; ULN is replaced by the mean baseline values obtained prior to irAE onset and increases should be proportionate to this modified baseline&#46;</p><p id="para0022" class="elsevierStylePara elsevierViewall">In this paper&#44; we considered patients with IMLI those having hepatotoxicity grade 3 or 4 according to CTCAE plus patients with ALP &#8805;2 X ULN and&#47;or Bil-T &#8805; 2&#46;5 mg &#40;according to DILIN&#41; while on ICIs or after cessation of ICI therapy&#46; Given the lack of specific biomarkers&#44; the diagnosis of IMLI was an exclusion diagnosis&#44; so exclusion of other reasons for its occurrence were considered&#44; namely hepatic metastasis&#44; evaluation of auto antibodies &#40;antinuclear antibodies&#44; anti-smooth muscle antibodies&#44; anti-actin antibodies&#44; namely anti-F-actin&#44; anti-soluble liver antigen&#47;liver pancreas antibodies&#44; anti-neutrophil cytoplasmic antibodies&#44; anti-mitochondrial antibodies&#44; anti-DNA antibodies&#44; anti-liver-kidney microsomal-1 and 3 antibodies&#44; anti-liver cytosol antibody-1&#41; and virologic serology &#40;namely for hepatitis A&#44; B&#44; C and E&#41;&#46;</p><p id="para0023" class="elsevierStylePara elsevierViewall">The pattern of liver injury &#40;LI&#41; was classified using the R value &#40;ratio of serum activity of ALT to ALP&#41;&#58; &#8216;hepatocellular&#8217; when there is a 5-fold or higher rise in ALT alone or when R is 5 or more&#59; &#8216;cholestatic&#8217; when there is a 2-fold or higher rise in ALP alone or when R is 2 or less&#59; &#8216;mixed&#8217; when R is between 2 and 5&#46;</p><p id="para0024" class="elsevierStylePara elsevierViewall">The peak liver biochemistry test results were recorded as the maximum values after meeting LI criteria&#59; normalisation of liver biochemistries was determined when the abnormal lab test returned to ALT &#60; 5 x ULN&#44; ALP &#60;2 x ULN or&#47;and Bil-T &#60; 2&#46;5 x ULN&#46; Laboratory results performed within the 3 months preceding ICI initiation were reviewed to exclude patients who had pre-ICI ALT &#8805; 3 X ULN &#40;CTCAE grade 1 or higher&#41;&#44; typically used by oncologists as a threshold to determine eligibility for ICI initiation&#46;</p><p id="para0025" class="elsevierStylePara elsevierViewall">Clinical signs and symptoms at the time of hepatotoxicity were noted &#40;abdominal pain&#44; fever&#44; jaundice and ascites&#41;&#46; When available&#44; liver histology&#39;s were assessed&#46;</p><p id="para0026" class="elsevierStylePara elsevierViewall">Previous hepatic disease was defined using evidence from imagiological&#44; histological or analytical data&#59; hepatic disease was then categorized according to medical records&#44; imagiological&#44; endoscopic&#44; fibroscan&#44; analytical and clinical criteria&#46; All patients had an abdominal ultrasound or computed tomography before ICI initiation&#44; to determine the presence of focal lesions in the liver or biliary tracts&#46;</p><p id="para0027" class="elsevierStylePara elsevierViewall">Outcomes assessed included ICI &#40;1&#41; treatment modifications&#44; namely a&#41; definitive suspension&#44; b&#41; transitory suspension&#44; c&#41; dose modification&#59; &#40;2&#41; treatment with steroids and&#47;or &#40;3&#41; need for other immunosuppressive treatments &#40;4&#41; requirement for hospitalization or intensive care unit admission&#59; &#40;5&#41; occurrence of liver failure &#40;6&#41; recurrence of liver injury after ICI rechallenge&#59; &#40;6&#41; death related to IMLI&#46;</p></span><span id="sec0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">2&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0015">Statistical analysis</span><p id="para0028" class="elsevierStylePara elsevierViewall">Descriptive statistics were calculated using mean &#40;standard deviation &#91;sd&#93;&#41; or median &#40;range&#41; for normally and nonnormally distributed data&#44; respectively&#46;</p></span></span><span id="sec0007" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3</span><span class="elsevierStyleSectionTitle" id="cesectitle0016">Results</span><span id="sec0008" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;1</span><span class="elsevierStyleSectionTitle" id="cesectitle0017">General characteristics</span><p id="para0029" class="elsevierStylePara elsevierViewall">There were 151 ICI recipients during the study period&#44; the majority were men &#40;76&#44;8&#37;&#41;&#46; Of these&#44; 5 received anti&#8211;CTLA-4 therapy&#44; 145 received anti&#8211;PD-1&#47;PD-L1 therapy&#44; and 1 received combination therapy &#40;anti-CTLA-4 plus anti-PD1&#41;&#46; Overall population characteristics are detailed in <a class="elsevierStyleCrossRef" href="#tbl0001">Table&#160;1</a>&#46; Patients had a median age at the beginning of treatment of 64 years &#40;IQR 16&#41;&#46; Lung cancer was the most common underlying malignancy &#40;48&#37;&#41;&#46; Forty-seven all grade nonhepatic irAEs were recorded&#44; with skin toxicities being the most common &#40;28&#37;&#41;&#44; followed by endocrine &#40;26&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0030" class="elsevierStylePara elsevierViewall">Eight patients developed liver injury during or after ICI treatment&#44; however 5 were not considered to have IMLI because they had hepatic metastasis &#40;<a class="elsevierStyleCrossRef" href="#fig0001">figure&#160;1</a>&#41;&#46; Detailed clinical information of patients who developed liver injury is available on supplementary <a class="elsevierStyleCrossRef" href="#tbl0002">table&#160;2</a>&#46;</p><elsevierMultimedia ident="fig0001"></elsevierMultimedia></span><span id="sec0009" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;2</span><span class="elsevierStyleSectionTitle" id="cesectitle0018">Immune-mediated liver injury</span><p id="para0031" class="elsevierStylePara elsevierViewall">Regarding the 3 IMLI patients&#44; 2 were men&#59; mean age of 63&#46;7 years&#46; General characteristic of IMLI are presented in <a class="elsevierStyleCrossRef" href="#tbl0002">table&#160;2</a>&#46; None had pre-existing liver injury&#46; Concerning their baseline hepatic biochemistries they presented a median ALT 17 U&#47;L&#44; AST 22 U&#47;L&#44; ALP 82 U&#47;L and GGT 26 U&#47;L&#46; The median duration from ICI initiation to IMLI was 84 days and&#47;or 4 cycles of ICI&#46; One patient registered IMLI one month after nivolumab suspension&#46; Peak levels of laboratory tests included a median ALT 254 U&#47;L &#40;5 x ULN&#41;&#44; ALP 627 U&#47;L &#40;4 x ULN&#41; and T-Bil 0&#46;67 mg&#47;dL&#46; No patient presented clinical signs or symptoms&#44; namely fever&#44; abdominal pain or jaundice&#46; All patients presented a cholestatic pattern of IMLI and none was submitted to liver biopsy&#46; Two patients suspended ICI treatment and all were submitted to steroid therapy&#46; No patient required further immunosuppressive or other additional therapy&#46; A favourable outcome was seen in all patients and the median time to hepatic biochemistries normalization was 150 days&#46;</p><p id="para0032" class="elsevierStylePara elsevierViewall">No patient presented clinical symptoms&#44; and there was no need for hospital admittance in any case&#46; No liver failure occurred and no IMLI death-related was reported&#46;</p><p id="para0033" class="elsevierStylePara elsevierViewall">One patient was submitted to ICI rechallenge with the same therapy and dosage with no recurrence of the liver injury&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;3</span><span class="elsevierStyleSectionTitle" id="cesectitle0019">Hepatic metastasis and liver injury</span><p id="para0034" class="elsevierStylePara elsevierViewall">Regarding the 5 patients with hepatic metastasis and liver injury&#44; 2 were men&#59; median age of 53 years&#46; Its characteristic are detailed in <a class="elsevierStyleCrossRef" href="#tbl0004">Table&#160;4</a>&#46; Their baseline hepatic biochemistries were median ALT 56 U&#47;L&#44; AST 34 U&#47;L&#44; ALP 128 U&#47;L and GGT 148 U&#47;L&#46;</p><p id="para0035" class="elsevierStylePara elsevierViewall">The median duration from ICI initiation to liver injury was 45 days and&#47;or 2 cycles of ICI&#46; Peak levels of laboratory tests included a median ALT 232 U&#47;L &#40;5 x ULN&#41;&#44; ALP 750 U&#47;L &#40;6 x ULN&#41; and Bil-T 0&#46;9 mg&#47;dL&#46; Four patients presented a cholestatic and one hepatocellular pattern of liver injury&#46; Four patients suspended ICI treatment and 2 were submitted to steroid therapy&#46;</p><p id="para0036" class="elsevierStylePara elsevierViewall">No patient presented clinical signs or symptoms&#44; namely fever&#44; abdominal pain or jaundice&#46;</p><p id="para0037" class="elsevierStylePara elsevierViewall">We would like to individualize a specific case &#40;patient 7 on supplementary table 1&#41; of a 62-year-old female patient with lung cancer that developed a hepatocellular liver injury 2 cycles after pembrolizumab&#46; There was no evidence of hepatic metastasis before treatment&#46; She was considered to have IMLI since other aetiologies were excluded and absence of hepatic metastasis was reassured with abdominal ultrasound&#44; which prompt the beginning of steroids&#46; The absence of response to steroids prompted a hepatic biopsy&#44; which complicated with haemorrhagic shock and diffuse liver metastasis was diagnosed intra-operatively&#46;</p><p id="para0038" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0004">Table&#160;4</a> is a comparative presentation of features of IMLI versus liver injury in patients with liver metastasis&#46;</p></span><span id="sec0011" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">3&#46;4</span><span class="elsevierStyleSectionTitle" id="cesectitle0020">Previous liver disease and liver injury</span><p id="para0039" class="elsevierStylePara elsevierViewall">There were 37 patients with liver conditions before ICI initiation&#58; 27 had liver metastasis&#44; 3 had hepatic steatosis defined by imaging&#44; 2 had previous exposure to hepatitis B virus but no active infection and no current treatment&#44; 4 had a past of chronic hepatitis C virus infection&#44; of those 4 with fibroscan &#8804;9&#44;5 and 1 with FS&#62;9&#44;5&#46; One patient presented with non-treated chronic C hepatitis&#59; one patient had cirrhosis of other causes and one patient had hepatocellular carcinoma &#40;which was not the tumour undergoing treatment&#41;&#46; All patients with cirrhosis were Child-Pugh A&#46;</p><p id="para0040" class="elsevierStylePara elsevierViewall">Only one patient with previous hepatic disease presented with grade 2 liver injury &#40;<a class="elsevierStyleCrossRef" href="#fig0001">figure&#160;1</a>&#41;&#58; 50-year-old male with untreated chronic C hepatitis&#44; who also had previous exposure to hepatitis B virus &#40;negative HBs-Ag&#44; positive anti-HBc and positive anti-HBs&#41; but no active infection&#46; He was submitted to pembrolizumab in the context of lung cancer&#46; In the beginning of treatment&#44; the patient presented detectable HCV viral load&#44; and developed grade 2 liver injury after 4 cycles of therapy as well as an increase in HCV virus load&#44; leading to treatment suspension during 2 cycles&#44; which resulted in an improved analytical&#46; He was rechallenged in the 7<span class="elsevierStyleSup">th</span> cycle and completed a total of 16 cycles without any relapsed increase in liver enzymes&#46;</p></span></span><span id="sec0012" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">4</span><span class="elsevierStyleSectionTitle" id="cesectitle0021">Discussion</span><p id="para0041" class="elsevierStylePara elsevierViewall">In this retrospective&#44; single&#8208;centre study&#44; we describe a comprehensive serological&#44; chronological&#44; and clinical data of a set of patients with checkpoint inhibitor irAE&#46; Similar real-world evaluations have been made over the last years in different regions of the globe &#40;<a class="elsevierStyleCrossRef" href="#tbl0004">Table&#160;4</a>&#41;&#46; Over a 4-year follow up&#44; 2&#37; of ICI patients developed hepatotoxicity ICI-related grade 3 or 4 according to both CTCAE and DILIN criteria&#44; one patient under pembrolizumab and two under nivolumab&#46; This data confirms the uncommon occurrence of this Drug Induced Liver Injury &#40;DILI&#41;&#44; which has been reported in 1&#8211;10&#37; of patients during ICI monotherapy <a class="elsevierStyleCrossRefs" href="#bib0010">&#91;10&#8211;13&#93;</a>&#46; IMLI occurs less often with anti-PD-1 ICI alone&#44; with a reported incidence of 1&#8211;4&#37; of patients <a class="elsevierStyleCrossRef" href="#bib0004">&#91;4&#93;</a>&#44; which is the likely explanation of our low prevalence of IMLI&#44; since most patients were treated with this drug class&#46; Marie-L&#233;a Gauci et&#160;al&#46; <a class="elsevierStyleCrossRef" href="#bib0014">&#91;14&#93;</a> reported the occurrence of immune related hepatoxicity &#8805;grade 3 on 21 of 339 patients &#40;6&#37;&#41; with advanced melanoma&#46; Of them&#44; seven &#40;8&#37;&#41; were under anti-CTLA&#44; 4 &#40;1&#46;7&#37;&#41; under anti-PD-1 &#40;nivolumab n&#160;&#61;&#160;3&#44; pembrolizumab&#61; 1&#41; and 10 &#40;38&#37;&#41; under combination &#40;ipilimumab plus nivolumab&#41;&#46;</p><p id="para0042" class="elsevierStylePara elsevierViewall">Given the lack of specific biomarkers&#44; the diagnosis of DILI remains an exclusion diagnosis&#46; In our population all liver injury cases were diagnosed based on analytics since no patients presented clinical symptoms&#46; In fact&#44; asymptomatic liver biochemical anomalies are the most common presentation of IMLI <a class="elsevierStyleCrossRef" href="#bib0015">&#91;15&#93;</a>&#46; However&#44; the presentation of anti-CTLA-4-related liver injury remains highly heterogeneous&#44; ranging from a mild rise in AST levels to fulminant liver failure <a class="elsevierStyleCrossRef" href="#bib0016">&#91;16&#93;</a>&#46;</p><p id="para0043" class="elsevierStylePara elsevierViewall">IMLI characterization varies according to the type of liver injury criteria used&#46; CTCAE and DILIN criteria disagree on what is conventionally considered a serious liver injury&#46; Consequently&#44; ICI-induced hepatoxicity&#39;s approach to monitoring and managements is a challenge for hepatologists and oncologists&#46; Grading systems&#8217; discrepancies require clear identification&#46; Furthermore&#44; it underlines that while ICI-induced hepatotoxicity is a form and probably represents a new subset of DILI&#44; since elevated bilirubin is seldom observed&#46; In this paper&#44; we opted to use a conjugation of both CTCAE and DILIN criteria&#46; As such&#44; we included all patients with CTCAE hepatotoxicity grade 3-4 and patients with FA &#8805; 2 x ULN e&#47; ou Bil-T &#8805;2&#44;5 x ULN&#46;</p><p id="para0044" class="elsevierStylePara elsevierViewall">Despite not having a standard biochemical signature the biochemistry pattern of IMLI has typically been reported as a hepatocellular injury&#46; <a class="elsevierStyleCrossRef" href="#bib0017">&#91;17&#93;</a> In a Japanese population treated with ICI <a class="elsevierStyleCrossRef" href="#bib0013">&#91;13&#93;</a> with all grade liver injury&#44; cholestatic and mixed-type liver injuries were more frequent than the hepatocellular type&#44; and one case showed bile duct dilation on imaging tests&#46; In our population&#44; all 3 patients with IMLI presented with a cholestatic pattern&#44; and in one case there was bile duct dilation on imaging tests &#40;MRCP and CT&#41;&#44; with no other features suggesting biliary obstruction&#46; ERCP exposed common bile duct and intrahepatic bile duct dilation without an obstructive cause&#46; He was submitted to steroids and evolved favourably with normalization of hepatic biochemistry&#46; Hepatic irAEs with abnormal image findings in the bile ducts have been reported alongside with ICI-associated cholangitis&#44; but their incidence is rare <a class="elsevierStyleCrossRefs" href="#bib0018">&#91;18&#8211;21&#93;</a>&#46;</p><p id="para0045" class="elsevierStylePara elsevierViewall">A case report on biliary obstruction in a patient under nivolumab&#44; reported obstruction resolution after high-dose prednisone administration&#44; favouring its immune mediated origin&#46; Similar to our report&#44; no gallstone or other aetiology were detected on MRCP or ERCP&#59; there was no history of hepatic&#47;biliary&#47;pancreatic diseases or abdominal surgery and no bacterial infection was documented&#59; however in that reported case&#44; biliary obstruction persisted after treatment with antibiotics and elevation of AST&#44; ALT&#44; and ALP levels also recurred until initiation of prednisone <a class="elsevierStyleCrossRef" href="#bib0019">&#91;19&#93;</a>&#46; Vincent Cheung etal&#46; <a class="elsevierStyleCrossRef" href="#bib0022">&#91;22&#93;</a> also reported a case of cholestatic IMLI&#44; the patient underwent magnetic resonance cholangiopancreaticogram as well as liver biopsy&#44; that demonstrated bilobar intrahepatic bile duct structuring and ectasia&#44; and portal based mixed inflammation with minimal lobulitis&#46; The cholestasis was responsive both to steroid and ursodeoxycholic acid&#46; Al Hepatic irAEs-related bile duct disorders might occur at the microscopic level&#46; PD-1 ligands &#40;PD-L1 and PDL2&#41; are expressed by biliary epithelial cells which does not occur for CLTA-4 ligands &#40;B7 &#40;CD80 or CD86&#41; molecules <a class="elsevierStyleCrossRef" href="#bib0023">&#91;23&#93;</a>&#46; Cholestatic liver injury was more frequent in our patients&#44; probably due anti-PD1 use in all cases&#46; Such findings may indicate that anti-PD-1 or PD-L1&#8217;s inhibition of the immune checkpoint pathway may induce biliary disorder in the hepatic irAE&#46; On the other hand the pathogenesis of ICP-related biliary injury is unknown and the lack of immune mediated liver injury features have been reported <a class="elsevierStyleCrossRef" href="#bib0021">&#91;21&#93;</a>&#44; what could suggest involvement of mechanisms distinct from those of immune-mediated hepatitis&#46; It would be useful to correlate the biochemical patterns to histologic features&#44; to more fully characterize patterns of possible liver injury due to ICI therapy&#46;</p><p id="para0046" class="elsevierStylePara elsevierViewall">The timeframe for irAE development after treatment initiation is within the first few weeks&#46; Even so&#44; they may present at any time including posterior to ICB therapy&#39;s interruption <a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a> as happened with one of our patients that presented IMLI one month after ICI nivolumab suspension&#46; The terminal half-life of nivolumab has been reported to be 12&#8211;20 days <a class="elsevierStyleCrossRef" href="#bib0024">&#91;24&#93;</a>&#46; Previous report shows that prolonged nivolumab binding to T lymphocytes was detected more than 20 weeks after the last infusion&#44; regardless of the total number of nivolumab infusions <a class="elsevierStyleCrossRef" href="#bib0025">&#91;25&#93;</a>&#46; Considering this&#44; these patients&#8217; careful follow-up should extend beyond ICIs administration is finalized&#46; On our cohort&#44; one patients developed IMLI 3 and other 6 cycles after ICI&#44; which in accordance to Ethan D&#46; Miller et&#160;al&#46; <a class="elsevierStyleCrossRef" href="#bib0012">&#91;12&#93;</a> who reported a median of 3 ICI infusions to hepatoxicity development&#46;</p><p id="para0047" class="elsevierStylePara elsevierViewall">In our cohort&#44; liver biopsy was obtained in only 1 patient who presented a refractory liver injury to steroids&#46; This low rate may reflect concerns about risks of biopsy&#44; or that a biopsy and referral to a hepatologist were not considered&#46; This patient&#39;s liver histology presented no inflammatory infiltrated and no portal fibrosis was identified&#59; diffuse intralobular macrovesicular steatosis with hepatocyte ballooning and occasional Mallory hyaline bodies without neutrophilic lobulitis&#46; Steatosis and features of sustained cholestasis were identified&#44; without the most common findings of immune mediated liver injury&#46; The liver biopsy complicated with haemorrhagic shock and a diffuse liver metastization was diagnosed intraoperatively&#44; despite normal previous imaging exams&#46; As such&#44; poor response to steroid therapy might also be a criterion for a more detailed study&#44; especially before implementing new immunosuppressing therapies&#46; In other reports there was evidence that hepatotoxicity caused by anti-CTLA-4 drugs showed a specific pattern of granulomatous hepatitis associated with severe lobular necrotic and inflammatory activity&#44; fibrin deposits and central vein endothelitis&#46; For anti-PD1&#47;PD-L1 immunotherapy recipients&#44; liver damage was more heterogenous&#44; involving lobular and periportal activity&#46; ICI&#39;s liver injury differs to the typically observed in autoimmune hepatitis&#44; since characteristic features are lacking such as plasma cell infiltration&#44; severe interface hepatitis&#44; piecemeal necrosis and rosette formation&#46; As such&#44; the term autoimmune-hepatitis should be dismissed in favour of immune-mediated hepatitis&#46; Adding to its role in diagnosis&#44; histological assessment may inform on the severity of liver damage and impact therapeutic decisions <a class="elsevierStyleCrossRef" href="#bib0011">&#91;11&#93;</a>&#46;</p><p id="para0048" class="elsevierStylePara elsevierViewall">In our cohort&#44; all three patients with IMLI were treated with steroid therapy&#46; One patient permanently suspended treatment after IMLI&#59; one suspended treatment briefly and after favourable evolution was rechallenged&#59; and a third patient maintained treatment with ICI&#46; As shown&#44; patient&#39;s approach was not uniform but did not result in different outcomes&#44; since all patients improved&#46; This reflects that the optimal management of irAEs&#44; including hepatotoxicity&#44; is yet to be determined&#46; According to current recommendations for grade 3 or 4 hepatotoxicity&#44; checkpoint inhibitor therapy should be permanently discontinued&#44; and corticosteroids started&#46; If there is no response to corticosteroids within 2&#8211;3 days&#44; a second immunosuppressant may be added <a class="elsevierStyleCrossRef" href="#bib0010">&#91;10&#93;</a>&#46; However some articles advocate a more conservative approach&#44; arguing that spontaneous improvement in liver tests may happen after suspending immunotherapy without any corticosteroid administration &#91;<a class="elsevierStyleCrossRef" href="#bib0011">11</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0015">15</a>&#93;&#46;</p><p id="para0049" class="elsevierStylePara elsevierViewall">As stated above&#44; one patient was submitted to rechallenge with the same ICI &#40;nivolumab at the same dosage&#41;&#46; Other similar series have demonstrated a safer rechallenge approach <a class="elsevierStyleCrossRef" href="#bib0026">&#91;26&#93;</a>&#46; In Marie-L&#233;a et&#160;al&#46; cohort immunotherapy was resumed in 8 patients after grade 1 achievement without hepatitis relapse&#58; the same immunotherapy for 2 patients &#40;9&#46;5&#37;&#41; and another class of immunotherapy for the 6 remaining patients &#40;28&#46;6&#37;&#41;&#46; Ethan D&#46; Miller et&#160;all <a class="elsevierStyleCrossRef" href="#bib0012">&#91;12&#93;</a> reported rechallenge in 31 patients after hepatoxicity &#8805;3&#46; Those who initially received monotherapy were either given the same regimen or received a medication from a different class but no one who initially received monotherapy was rechallenged with combination therapy&#46; Only 8 of the patients &#40;26&#37;&#41; who reinitiated ICI therapy exhibited recurrent hepatotoxicity&#59; all 8 initially had grade 3 hepatotoxicity&#46; Currently&#44; limited data is available on rechallenge&#44; which is explained by the usual prohibition of rechallenge on clinical trials providing most data <a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a>&#46; In Pollack et&#160;al&#46;&#8217;s retrospective study&#44; among recipients of combination ICI therapy discontinued due to a range of irAEs &#40;36&#37; had hepatotoxicity and 24&#37; of those had CTCAE grade 3 or grade 4 hepatotoxicity&#41;&#44; anti-PD1 therapy rechallenge led to hepatitis recurrence in 17&#37; &#40;7&#37; were CTACAE grade 3 or grade 4&#41; <a class="elsevierStyleCrossRef" href="#bib0027">&#91;27&#93;</a>&#46; An observational&#44; cross-sectional&#44; pharmacovigilance cohort study examined individual case safety reports from theWorld Health Organization database VigiBase&#46; This cohort study found a 28&#46;8&#37; recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI&#46; The recurrence rates for colitis&#44; hepatitis&#44; and pneumonitis were higher after rechallenge compared with other irAEs <a class="elsevierStyleCrossRef" href="#bib0028">&#91;28&#93;</a>&#46; Santini et&#160;al&#46; <a class="elsevierStyleCrossRef" href="#bib0029">&#91;29&#93;</a> retrospectively identified 68 patients with advanced non&#8211;small cell lung cancer who were treated with anti&#8211;PD-1 or anti&#8211;PD-L1 either as monotherapy or in combination with anti&#8211;CTLA-4&#46; Of these patients&#44; 38 &#40;55&#46;9&#37;&#41; received a rechallenge with an anti&#8722;PD-1 or anti&#8722;PD-L1 therapy alone&#46; Over a median follow-up of 14&#46;3 months&#44; the same irAE occurred in 26&#37; of the patients&#44; and any type of irAE occurred in 52&#37; of the patients after the ICI rechallenge&#46; The question of whether to administer ICI rechallenge is crucial&#46; Practical guidelines for irAE management are based on clinical observations and expert consensus&#44; but they do not discuss the possibility of a rechallenge&#46; Patients who present cancer progression after the discontinuation of an ICI for irAE occurrence may find an ICI rechallenge to be beneficial&#46; In the absence of specific recommendations&#44; the decision to rechallenge must be discussed in each case and may be considered for select patients&#46;</p><p id="para0050" class="elsevierStylePara elsevierViewall">Irene Tsung et&#160;al evaluated the cause of liver injury in patients under pembrolizumab treatment&#44; and they found only a minority of the liver injury cases were attributed to pembrolizumab hepatotoxicity &#40;29&#37;&#41; while cancerous replacement of the liver accounted for most of the other patients with benign or malignant biliary obstruction identified in 5&#46;7&#37;&#46; They demonstrate that patients who present with an acute hepatocellular or mixed injury pattern are more likely to be experiencing immune&#8208;mediated liver injury due to pembrolizumab but there was no particular serum ALT&#44; ALP&#44; or bilirubin level that reliably differentiated patients with DILI from other causes of liver injury &#91;<a class="elsevierStyleCrossRef" href="#bib0001">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0030">30</a>&#93; In our cohort we find 8 patients with liver injury grade 3 or 4 and only 3 patients attributable to immune mediated adverse effects&#44; being the majority associated with hepatic metastasis&#46; This data indicates that careful clinical assessment of the cause of liver injury is critical including contrast enhanced cross&#8208;sectional imaging of the liver to assess for tumour progression and to help ensure that the appropriate actions are undertaken&#44; namely the institution of immunosuppressive therapy&#46;</p><p id="para0051" class="elsevierStylePara elsevierViewall">In our population&#44; the presence of chronic liver disease or known liver injury &#40;excluding liver metastasis&#41; was not risk factors for IMLI onset&#46; However&#44; IMLI&#39;s low incidence is likely a limiting factor for this conclusion&#46; Defining pre-existing liver disease&#39;s accountability when assessing DILI is uncertain&#46; This prompts discussion on the best criteria to mark acute&#47;overlying injury in the background of some degree of chronic injury <a class="elsevierStyleCrossRef" href="#bib0031">&#91;31&#93;</a>&#46; Hepatology consults and liver biopsy in those with possible pre-existing liver injury&#44; should be both considered in future studies&#46; We report a patient with past HBV infection and untreated chronic HCV infection developing a grade 2 liver injury&#46; The adopted approach was to temporarily suspend treatment&#44; leading to favourable evolution&#46; The patient was then rechallenged and completed 16 ICI cycles without any increase in liver enzymes&#46; ICI therapies&#8217; clinical trials usually excluded patients with history of chronic viral infections&#44; namely HBV&#44; HCV and HIV&#46; Nevertheless&#44; some reports on ipilimumab administration for advanced melanoma suggest that its use in patients with pre-existing HBV and HCV infection might be effective and safe &#91;<a class="elsevierStyleCrossRef" href="#bib0032">32</a>&#44;<a class="elsevierStyleCrossRef" href="#bib0033">33</a>&#93;&#46; Such studies had patients with HBV infection treated with ipilimumab while simultaneously given either entecavir or tenofovir&#46; HCV patients&#44; on their turn&#44; were not under HCV treatment <a class="elsevierStyleCrossRef" href="#bib0034">&#91;34&#93;</a>&#46; A retrospective review of 23 Chinese patients with advanced melanoma under either ipilmumab&#44; pembrolizumab or combination therapy&#44; reported similar safety data&#46; Prior HBV infection was reported in eight patients&#44; and active HBV infection on three patients who being treated with concomitant entecavir <a class="elsevierStyleCrossRef" href="#bib0035">&#91;35&#93;</a>&#46;</p><p id="para0052" class="elsevierStylePara elsevierViewall">We conclude that clinically significant ICI-related hepatotoxicity was uncommon&#46; There was a cholestasis pattern predominance in liver injuries&#46; ICI proved to be safe in patients with previous hepatic diseases in our population&#46;</p><p id="para0053" class="elsevierStylePara elsevierViewall">Limitations to this retrospective paper are&#58; consideration only to exposure time without reporting ICI doses&#59; ICI clinical response was not assessed&#59; the lack of histological studies&#59; the absence of alcohol intake which is a possible underlying factor por hepatic abnormalities&#46;</p><elsevierMultimedia ident="tbl0002"></elsevierMultimedia><elsevierMultimedia ident="tbl0003"></elsevierMultimedia><elsevierMultimedia ident="tbl0004"></elsevierMultimedia><p id="para0053a" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0002">Table&#160;2</a></p></span></span>"
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          "identificador" => "xres1761529"
          "titulo" => "Abstract"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "abss0001"
              "titulo" => "Introduction and objectives"
            ]
            1 => array:2 [
              "identificador" => "abss0003"
              "titulo" => "Materials and methods"
            ]
            2 => array:2 [
              "identificador" => "abss0005"
              "titulo" => "Results"
            ]
            3 => array:2 [
              "identificador" => "abss0006"
              "titulo" => "Conclusions"
            ]
          ]
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec1549124"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xpalclavsec1549125"
          "titulo" => "Abbreviations"
        ]
        3 => array:2 [
          "identificador" => "sec0001"
          "titulo" => "Introduction"
        ]
        4 => array:3 [
          "identificador" => "sec0002"
          "titulo" => "Materials and methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0003"
              "titulo" => "Patients"
            ]
            1 => array:2 [
              "identificador" => "sec0004"
              "titulo" => "Clinical information"
            ]
            2 => array:2 [
              "identificador" => "sec0005"
              "titulo" => "Liver injury definition"
            ]
            3 => array:2 [
              "identificador" => "sec0006"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        5 => array:3 [
          "identificador" => "sec0007"
          "titulo" => "Results"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0008"
              "titulo" => "General characteristics"
            ]
            1 => array:2 [
              "identificador" => "sec0009"
              "titulo" => "Immune-mediated liver injury"
            ]
            2 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Hepatic metastasis and liver injury"
            ]
            3 => array:2 [
              "identificador" => "sec0011"
              "titulo" => "Previous liver disease and liver injury"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0012"
          "titulo" => "Discussion"
        ]
        7 => array:2 [
          "identificador" => "xack622262"
          "titulo" => "Funding"
        ]
        8 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-12-06"
    "fechaAceptado" => "2021-04-30"
    "PalabrasClave" => array:1 [
      "en" => array:2 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1549124"
          "palabras" => array:6 [
            0 => "Immunotherapy"
            1 => "cancer"
            2 => "Hepatotoxicity"
            3 => "Drug-Related Side Effects and Adverse Reactions"
            4 => "Drug Induced Liver Injury"
            5 => "Immune-related adverse event"
          ]
        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec1549125"
          "palabras" => array:5 [
            0 => "ICB"
            1 => "ICI"
            2 => "IMLI"
            3 => "irAE"
            4 => "LI"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abss0001" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0002">Introduction and objectives</span><p id="spara010" class="elsevierStyleSimplePara elsevierViewall">Immune Checkpoint Inhibitors &#40;ICI&#41; have shifted the paradigm of cancer therapy treatment&#46; Despite their efficacy&#44; ICIs may induce immune-related adverse events &#40;irAE&#41;&#44; which can affect various organs&#44; namely the liver&#46; This study intends to perform a comprehensive clinical description of the hepatic irAEs associated with ICI in a Portuguese population of a tertiary hospital centre&#46;</p></span> <span id="abss0003" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0004">Materials and methods</span><p id="spara011" class="elsevierStyleSimplePara elsevierViewall">A retrospective analysis of patients who developed immune-mediated liver injury &#40;IMLI&#41;&#44; among a cohort of patients treated with ICIs between March 15<span class="elsevierStyleSup">th</span> of 2015 and December 15<span class="elsevierStyleSup">th</span> of 2019 in a tertiary hospital&#46; We used both Common Terminology Criteria for Adverse Events &#40;CTCAE&#41; and Drug&#8208;Induced Liver Injury Network &#40;DILIN&#41; criteria to define liver injury&#46;</p></span> <span id="abss0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0006">Results</span><p id="spara012" class="elsevierStyleSimplePara elsevierViewall">Among 151 patients&#44; eight &#40;5&#46;3&#37;&#41; patients developed liver injury grade &#8805;3&#44; of which five had hepatic metastasis&#46; As such&#44; only 3 cases were classified as IMLI&#46; All IMLI presented with cholestasis pattern&#59; the median duration from ICI initiation to IMLI was 84 days and&#47;or 4 ICI cycles&#59; one patient registered IMLI one month after nivolumab suspension&#59; all were treated with steroids and one was successfully submitted to ICI re-challenge&#59; a favourable outcome was seen in all patients&#59; the median time to hepatic biochemistries normalization was 150 days&#46; Among 10 patients with previous hepatic conditions&#44; only one developed liver injury grade 2&#46;</p></span> <span id="abss0006" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cesectitle0007">Conclusions</span><p id="spara013" class="elsevierStyleSimplePara elsevierViewall">Clinically significant ICI-related hepatotoxicity was uncommon&#59; Immune-mediated liver injury may present a cholestatic pattern predominance&#46; There was a low rate of liver injury of any kind in patients with previous hepatic disease while on ICI&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abss0001"
            "titulo" => "Introduction and objectives"
          ]
          1 => array:2 [
            "identificador" => "abss0003"
            "titulo" => "Materials and methods"
          ]
          2 => array:2 [
            "identificador" => "abss0005"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abss0006"
            "titulo" => "Conclusions"
          ]
        ]
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="para0055a" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="ecom0001"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix"
            "titulo" => "Supplementary materials"
            "identificador" => "sec0014"
          ]
        ]
      ]
    ]
    "multimedia" => array:6 [
      0 => array:8 [
        "identificador" => "fig0001"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1307
            "Ancho" => 2749
            "Tamanyo" => 178117
          ]
        ]
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0001"
            "detalle" => "Figure "
            "rol" => "short"
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">&#8211; Distribution of patients with liver injury according to its aetiology&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "tbl0001"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0002"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara003" class="elsevierStyleSimplePara elsevierViewall">Legend&#44; ALP - alkaline phosphatase&#59; ALT - alanine aminotransferase&#59; AST - aspartate aminotransferase&#59; Bil-T - total bilirubin&#59; GGT - gamma-glutamyltransferase&#59; IQR - interquartile range&#59; irAE - immune-related adverse event&#59; n &#8211; number&#59; sd - standard deviation&#59; yr &#8211; years&#59;</p>"
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              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0002"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0003"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Age &#40;yr&#41;&#44; mean &#40;sd&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;4 &#40;11&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0005"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Sex&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0006"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">35 &#40;23&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116 &#40;76&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Active smoking&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92 &#40;60&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Charlson Index&#44; mean &#40;sd&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46;81 &#40;2&#46;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Autoimmune disease&#44; n&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0016"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;0&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0017"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Cancer&#44; n&#40;&#37;&#41;</span></td></tr><tr title="table-row"><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0019"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74&#40;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Genitourinary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#40;19&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Head and neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#40;13&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Gastrointestinal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0028"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Other solid tumours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0029"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0030"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Haematological malignancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0031"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0032"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Median duration of ICI treatment&#44; weeks &#40;IQR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0033"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">23&#40;45&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0034"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Checkpoint inhibitor&#44; n&#40;&#37;&#41;</span></td></tr><tr title="table-row"><a name="en0035"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Anti-CTLA-4 monotherapy &#40;ipilimumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0036"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0037"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Anti-PD-1 monotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0038"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140&#40;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0039"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nivolumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0040"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80 &#40;53&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0041"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Pembrolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0042"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60 &#40;39&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0043"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Anti- PD-L1 monotherapy &#40;atezolimumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0044"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0045"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Combination therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0046"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#40;0&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0047"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Baseline hepatic biochemistries&#44; median &#40;IQR&#41;</span></td></tr><tr title="table-row"><a name="en0048"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0049"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0050"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0051"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">19&#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0052"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ALP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0053"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#40;49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0054"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">GGT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0055"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#40;37&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0056"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="2" align="left" valign="top"><span class="elsevierStyleBold">Pre-existing liver disease&#44; n&#40;&#37;&#41;</span></td></tr><tr title="table-row"><a name="en0057"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Liver metastasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0058"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#40;17&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0059"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Steatosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0060"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0061"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Non-cirrhotic liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0062"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0063"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0064"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#40;3&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0065"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Other irAEs&#44; n&#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0066"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0067"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Enterocolitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0068"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;2&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0069"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0070"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#40;8&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0071"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Endocrine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0072"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#40;7&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0073"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0074"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#40;4&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0075"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Others&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0076"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#40;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara002" class="elsevierStyleSimplePara elsevierViewall">- Selected clinical characteristics of patients submitted to ICIs &#40;N &#61;151 patients&#41;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0003"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0003"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara005" class="elsevierStyleSimplePara elsevierViewall">Legend&#44; ALP - alkaline phosphatase&#59; ALT - alanine aminotransferase&#59; ICI &#8211; Immune checkpoint inhibitors&#59;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0077"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0078"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0079"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0080"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0081"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Gender&#44; age &#40;years&#41;&#44; tumour type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0082"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">F 66Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0083"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">M60Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0084"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">M65Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0085"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ICI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0086"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Pembrolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0087"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nivolumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0088"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Nivolumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0089"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Clinical symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0090"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0091"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0092"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0093"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Time to IMLI &#40;days&#59; number of cycles&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0094"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">65 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0095"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1 month after ICI suspension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0096"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">846&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0097"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Peak level of ALT &#40;U&#47;L&#41;&#44; ALP &#40;U&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0098"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ALT 180ALP 550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0099"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ALT 615ALP 1300&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0100"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">AST 254ALP 627&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0101"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Liver injury patter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0102"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Cholestatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0103"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Cholestatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0104"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Cholestatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0105"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Imagiological features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0106"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0107"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0108"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Common bile duct dilation without obstructive cause&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0109"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ICI suspension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0110"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0111"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0112"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0113"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Steroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0114"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0115"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0116"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0117"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">ICI Rechallenge&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0118"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0119"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0120"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0121"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Post-rechallenge recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0122"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0123"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0124"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara004" class="elsevierStyleSimplePara elsevierViewall">&#8211; Immune-mediated liver injury &#40;IMLI&#41; features</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0002"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0004"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara007" class="elsevierStyleSimplePara elsevierViewall">Legend ALP - alkaline phosphatase&#59; ALT - alanine aminotransferase&#59; AST - aspartate aminotransferase&#59; Bil-T - total bilirubin&#59; IQR - interquartile range&#59; irAE - immune-related adverse event&#59; LI &#8211; liver injury&#59; n &#8211; number&#59; sd - standard deviation&#59; yr &#8211; years&#59;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0125"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0126"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">IMLI &#40;N&#61;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0127"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Liver injury-metastasis related features &#40;N&#61;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0128"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Age &#40;yr&#41;&#44; median&#44; &#40;IQR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0129"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0130"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53 &#40;18&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0131"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="top">Sex&#44; n &#40;&#37;&#41;</td></tr><tr title="table-row"><a name="en0132"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0133"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0134"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0135"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0136"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0137"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 &#40;40&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0138"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Active smoking&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0139"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0140"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0141"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0142"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0143"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0144"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0145"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0146"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0147"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Number of cycles of ICI to LI&#44; median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0148"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0149"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0150"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">BASELINE HEPATIC BIOCHEMISTRIES&#44; median &#40;IQR&#41;</span></td></tr><tr title="table-row"><a name="en0151"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0152"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0153"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56 &#40;79&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0154"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">AST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0155"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0156"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;69&#44;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0157"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0158"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0159"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">128 &#40;287&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0160"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">GGT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0161"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0162"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142 &#40;522&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0163"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">PEAK LIVER BIOCHEMISTRIES&#44; median &#40;IQR&#41;</span></td></tr><tr title="table-row"><a name="en0164"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0165"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">254&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0166"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">232 &#40;275&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0167"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">ALP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0168"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">627&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0169"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">750 &#40;755&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0170"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Bil-T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0171"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&#44;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0172"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;9 &#40;9&#44;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0173"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead colgroup " colspan="3" align="left" valign="top"><span class="elsevierStyleBold">LIVER INJURY PATTERN&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><a name="en0174"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Cholestatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0175"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0176"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;80&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0177"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Hepatocellular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0178"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0179"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0180"></a><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="" valign="top">Mixed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0181"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0182"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara006" class="elsevierStyleSimplePara elsevierViewall">&#8211; Immune-mediated liver injury &#40;IMLI&#41; and liver injury-metastasis related features</p>"
        ]
      ]
      4 => array:8 [
        "identificador" => "tbl0004"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "alt0005"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spara009" class="elsevierStyleSimplePara elsevierViewall">Legend ICI &#8211; immune checkpoint inhibiotors&#59; IMLI &#8211; immune mediated liver injury&#59;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><a name="en0183"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0184"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Patients&#44; n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0185"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Geographic location&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0186"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Study period&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0187"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">IMLI Incidence &#40;grade 3-4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0188"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Latency to IMLI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0189"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">ICI discontinuation n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0190"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Steroids use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0191"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Time to hepatic biochemistries normalization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><a name="en0192"></a><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">Data on rechallenge&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><a name="en0193"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Marie-L&#233;a Gauci <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0194"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">339&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0195"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Europe &#40;France&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0196"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">April 2012 to December 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0197"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0198"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">63 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0199"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">20&#47;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0200"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">13&#47;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0201"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">37&#46;5days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0202"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">8&#47;21 without hepatitis relapse &#40;same immunotherapy for 2 patients and another class for the 6 remaining patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0203"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Ethan D&#46; Miller <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0002">&#91;2&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0204"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5762&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0205"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">USA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0206"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">January 2010 to March 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0207"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">2&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0208"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">62 days for patients submitted to steroids&#59; 44 days for patients not submitted to steroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0209"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">69&#47;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0210"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">67&#47;100&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0211"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">35 for patients submitted to steroids&#59; 19 days for patients not submitted to steroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0212"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">31&#47;100 Only 8 of the patients who reinitiated ICI therapy exhibited recurrent hepatotoxicity&#59;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0213"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Vincent Cheung <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0003">&#91;3&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0214"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">453&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0215"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Europe &#40;UK&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0216"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">December 2011 to 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0217"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0218"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">120 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0219"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0220"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">18&#47;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0221"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">- 20 days in patients submitted to steroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0222"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4&#47;20&#46; No recurrence&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0223"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Mar Riveiro-Barciela <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0004">&#91;4&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0224"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">414&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0225"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Europe &#40;Spain&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0226"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">January 2016 to December 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0227"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0228"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0229"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28&#47;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0230"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">28&#47;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0231"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">1&#46;5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0232"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">6&#47;11&#44; four of them continued to be treated with an anti-PD-1&#47;PD- L1 agent and two others previously treated with an anti-CTLA-4 were treated with an anti-PD-1&#47;PD- L1&#46; None presented recurrence of the irH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0233"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Koji Imoto <span class="elsevierStyleItalic">et al</span><a class="elsevierStyleCrossRef" href="#bib0005">&#91;5&#93;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0234"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">387&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0235"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0236"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">January 2014 to February 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0237"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0238"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">45&#46;5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0239"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0240"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">5&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0241"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">4-6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0242"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">-&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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ISSN: 16652681
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos