Effects of systemic chemotherapy on the liver

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"documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2010;9:144-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 60 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 26 "PDF" => 26 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Nonalcoholic fatty liver disease in asymptomatic obese women<a class="elsevierStyleCrossRef" href="#fn3">(a)</a>" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "144" "paginaFinal" => "149" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1292 "Ancho" => 1000 "Tamanyo" => 54052 ] ] "descripcion" => array:1 [ "en" => "Algorithm for the early clinical recognition of NAFLD. In the presence of obesity and diabetes, women aged <40 years would have a determination of triglycerides levels; if triglycerides are ≥ 300 mg/dL and healthy ALT levels ≥ 20 UIL, hepatic ultrasonography is mandatory; in the presence of steatosis and AST/ALT levels ≥ I, hepatic biopsy should be proposed." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Heriberto Rodriguez-Hernandez, Miriam Cervantes-Huerta, Jose Luis Gonzalez, María Dolores Marquez-Ramirez, Martha Rodriguez-Moran, Fernando Guerrero-Romero" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Heriberto" "apellidos" => "Rodriguez-Hernandez" ] 1 => array:2 [ "nombre" => "Miriam" "apellidos" => "Cervantes-Huerta" ] 2 => array:2 [ "nombre" => "Jose" "apellidos" => "Luis Gonzalez" ] 3 => array:2 [ "nombre" => "María" "apellidos" => "Dolores Marquez-Ramirez" ] 4 => array:2 [ "nombre" => "Martha" "apellidos" => "Rodriguez-Moran" ] 5 => array:3 [ "preGrado" => "MD, PhD" "nombre" => "Fernando" "apellidos" => "Guerrero-Romero" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119316527?idApp=UINPBA00004N" "url" => "/16652681/0000000900000002/v1_201907070740/S1665268119316527/v1_201907070740/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119316503" "issn" => "16652681" "doi" => "10.1016/S1665-2681(19)31650-3" "estado" => "S300" "fechaPublicacion" => "2010-04-01" "aid" => "71336" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Ann Hepatol. 2010;9:120-32" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 53 "formatos" => array:3 [ "EPUB" => 8 "HTML" => 18 "PDF" => 27 ] ] "en" => array:10 [ "idiomaDefecto" => true "titulo" => "Prevention of hepatocellular carcinoma" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "120" "paginaFinal" => "132" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Michael C. Kew" "autores" => array:1 [ 0 => array:2 [ "nombre" => "Michael C." "apellidos" => "Kew" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119316503?idApp=UINPBA00004N" "url" => "/16652681/0000000900000002/v1_201907070740/S1665268119316503/v1_201907070740/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Effects of systemic chemotherapy on the liver" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "133" "paginaFinal" => "143" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Giuliano Ramadori, Silke Cameron" "autores" => array:2 [ 0 => array:3 [ "nombre" => "Giuliano" "apellidos" => "Ramadori" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] 1 => array:3 [ "nombre" => "Silke" "apellidos" => "Cameron" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Department of Gastroenterology and Endocrinology, Georg-August-University Göttingen" "etiqueta" => "*" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 564 "Ancho" => 997 "Tamanyo" => 62033 ] ] "descripcion" => array:1 [ "en" => "A 62 years old patient with the first diagnosis of a cholangiocarcinoma in June 2006. The MRCP (A) showed a strong intrahepatic cholestasis with high bilirubin levels (E). Therefore a PTC was performed. The PTC (B) showed a dilation of the intrahepatic bile ducts and a subtotal stenosis of the DHC. In a “Rendezvous-technique” (PTC together with ERCP; C) it was possible to pass the DHC stenosis and place one stent in the right and one stent in the left main bile duct (D). The bilirubin levels decreased and a chemotherapy with gemcitabine was started. Actually the patient has further on normal bilirubin levels (E)." ] ] ] "textoCompleto" => "The Liver is the Central Organ of Intermediate Metabolism and is Crucial in Host DefenseThe liver is the central organ of the intermediate metabolism and is the main source of plasma proteins (e. g. albumin). The parenchymal cells, the hepatocytes, comprise about 80% of the liver mass and about 60% of the total number of the adult liver cell population.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>,<a class="elsevierStyleCrossRef" href="#bib0010">2</a> They are responsible for the organization and for the performance of intermediate metabolism, for the metabolic detoxification and for the excretion of waste products. Whilst for most drugs, hepatocyte function is drug-degradation, for some it is the activation of prodrugs. Therefore, a normal functioning hepatocyte is a prerequisite for the administration of chemotherapy. In case of abnormalities due to hepatocellular damage on the one hand, or to a high demand for hepatocellular biosynthesis on the other hand, this high-powered engine may get into trouble.For the correct execution and tight regulation of these processes, the spatial relationship of the hepa-tocytes with the different cellular structures of the liver, such as fenestrated sinusoidal endothelial cells, Kupffer cells, and bile canaliculi is important.Beneath the well known functions of the liver regarding intermediate metabolism and detoxification, there is another equally relevant function, the clea-rance function.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> About 80% of the body’s fixed tissue macrophages (von Kupffer cells) reside within the liver. The von Kupffer cells are in direct contact with the portal blood, streaming back from the gut or from the systemic circulation. This blood may be heavily loaded with toxic (lipopolysaccharide) or infectious agents (bacteria, viruses), cellular debris (e. g. from erythrocytes), undigested biomaterial or any other compounds that are not supposed to enter the systemic blood circulation. Scavenging of all this material is achieved in the liver by von Kupffer cell-and sinusoidal endothelial cell-endocytosis.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Moreover, humoral factors that are part of the innate immune system may ease hepatic clearance and maintain host-defense mechanisms. Changes in the function of the liver immune cells have been reported after cytotoxic chemotherapy.Alongside functional issues, obstruction of the bile duct system prior to chemotherapy presents a problem in cancer patients which has to be solved before chemotherapy is started (<a class="elsevierStyleCrossRef" href="#f0005">Figure I</a>). Disturbance of the bile flow leads in fact to reduction of the hepatocellular function and to reduced protein synthesis. The gastroenterologist is therefore the specialist again, who should be contacted in such cases.<elsevierMultimedia ident="f0005"></elsevierMultimedia>Basic Principles of Cytotoxic ChemotherapyChemotherapy as the main nonsurgical remedy of cancer treatment is generally based on the cytotoxic effect of natural or synthetic agents taking advantage of a higher vulnerability of cancer cells as compared to normal cells. However, normal cells may be affected by cytotoxic chemotherapy as well.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Suscep-tibility to chemotherapy is linked to the proliferative rate of a cell population as seen in bone marrow cells or mucosal cells with high replication rates. Inhibition of DNA replication and transcription via interference of cancer drugs either with the DNA strand, with enzymes involved in DNA metabolism or DNA substrates may rank as the most important principle of cancer treatment directly inhibiting cell proliferation.The Liver May Become A “Target” of and May Suffer From Cytotoxic ChemotherapyReplication of hepatocytes is low in normal liver, but may reach a high level during liver regeneration after massive hepatocellular death or partial hepa-tectomy.In the healthy liver, with its low replication rate, inhibition of hepatocellular replication during chemotherapy thus is not of primary matter. Nevertheless, systemic application of chemotherapeutics affecting DNA, RNA or protein synthesis, may affect hepatocellular function in several ways:Nausea and vomiting cause a reduction of nutrition; reduced uptake of nutrients has been shown to induce a shrinkage of the liver that may reach a reduction in liver cell mass of almost 50% under total starving. Normal food uptake after fasting has been shown to induce DNA synthesis in hepatocytes with cellular replication (DNA endoreplication) resulting in polyploidy and presence of several nuclei in the hepatocytes.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> However, even without a period of fas-ting, highly metabolically active hepatocytes need normal DNA and RNA synthesis for normal protein synthesis.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Impact of Cytotoxic Chemotherapy on Liver Function: Hepatocellular Dysfunction and Clinical ImplicationsMost drugs tend to be lipophilic compounds that are taken up readily by the liver but that cannot be excreted easily unchanged in bile or urine. Metabolic pathways are inducible and include a series of steps that alter the parent molecule, synthesize conjugates of the drug or its metabolite with a more water-soluble moiety and comprise energy-dependent pathways to excrete either the parent molecule or its conjugates into the bile.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Under chemotherapy, up to 85% of patients develop liver steatosis indicating disturbed lipid metabolism via altered lipoprotein synthesis in the hepato-cytes. An increase of the hepatocellular lipid content (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>) is responsible for higher vulnerability. The higher vulnerability may, in particular during repeated chemotherapy, induce irreversible hepato-cellular damage through recruitment of inflammatory cells.<elsevierMultimedia ident="f0010"></elsevierMultimedia>Elevation of serum aminotransferases represents a frequent event during or after cytotoxic chemotherapy. The hepatocellular sensibility to cytotoxic chemo-therapy depends on the particular chemotherapeutic agent, giving rise to a classification of agents with high or low potential hepatotoxicity (<a class="elsevierStyleCrossRef" href="#t0005">Table I</a>).<elsevierMultimedia ident="t0005"></elsevierMultimedia>Impairment of Liver Function During Cytotoxic Chemotherapy: Impact on Clearance FunctionAs described above, the liver is home of 80% of all fixed tissue macrophages of the body. It has to be assumed that this accumulation of mononuclear phagocytes in the liver reflects a high demand for clearance in this particular organ primarily conducted by Kupffer cells. The turnover of Kupffer cells has been debated for decades, and there is no final argument to what extent Kupffer cells are self-repli-cative or replaced by immigrating blood monocytes. The mitotic index of Kupffer cells is quite low, and increasing evidence has accumulated that Kupffer cells primarily derive from bone marrow cells.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Accordingly, a numerous population of transient mo-nocytes has been reported in normal liver.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> On the other hand, a large influx of blood monocytes is observed in the diseased liver.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> After chemotherapy with suppression of bone marrow cell replication, the supply of Kupffer cell precursor cells is disturbed. At the same time, epithelial cell replication in the gut is also suppressed. The increased permeability of the gut gives rise to a highly increased hepatic onflow of toxic and infectious agents demanding a faster turnover of hepatic macrophages. This divergency may result in an increased risk for infections. It has further been shown that cytotoxic chemotherapy impairs the phagocytotic activity of Kupffer ce-lls.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Reduced synthesis of humoral factors for host defense may also be critical in development of infections after cytotoxic chemotherapy.Drug-Induced Liver DiseaseDrug-induced liver disease can mimic all forms of acute and chronic hepatobiliary diseases. Liver injury is designated hepatocellular when the alanine transaminase (ALT) level is greater than 2 times the upper limit of normal (ULN) or the ALT/alkaline phosphatase (AP) ratio is ≥ 5; cholestatic when the AP is greater than 2 times ULN or the ALT/AP ratio is ≤ 2; and mixed when the ALT/AP ratio is 2 to 5 and the individual values are greater than 2 times ULN.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>,<a class="elsevierStyleCrossRef" href="#bib0070">14</a>Hepatic dysfunction under chemotherapy mainly consists of abnormal biologic liver tests indicating chronic cholestasis with elevation in the levels of bilirubin, alkaline phosphatase (AP), and gamma glutamyl transferase (yGT) with or without abnormal levels of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT). The predominant clinical presentations resemble acute icteric hepatitis or cholestatic disease.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>The development of hepatotoxicity is determined by the interplay of the toxic potential of the drug or its metabolites and the susceptibility of the patient as determined by genetic (i.e. extensive or poor me-tabolizer) and environmental factors.Risk factors for drug-induced liver disease include: age, gender, genetic or familial predisposition, drug interactions (concomitant drugs), cross-reactivity of different drugs which have not been tolerated in the past, alcohol (abuse), nutritional status and underlying liver or other diseases (i.e. viral hepatitis).<a class="elsevierStyleCrossRef" href="#bib0075">15</a> In cancer patients, causes of abnormal liver tests are further toxicity of anticancer drugs, toxicity of supportive medications, radiation-induced liver disease, tumor infiltration of the liver, Budd-Chiari syndrome, paraneoplatic syndrome, graft-versus-host disease (after stem cell transplantation), fungal liver disease, sepsis, and hemolysis.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Veno-Occlusive Disease of the LiverHigh-dose cytoreductive chemotherapy (as given before bone-marrow transplantation) which might be combined with radiotherapy, carries the serious risk for the development of veno-occlusive disease (VOD) of the liver.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> The clinical hallmarks for the on-setting of this disease are jaundice, painful hepatomegaly and fluid retention, accompanied by high elevation of aminotransferases and later ascites and hepatic encephalopathy. The basic pathophysiological mechanism of induction of VOD of the liver is supposed to be an injury of the endothelial cells of central veins and sublobular liver veins.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> A subsequent clotting activation results in occlusion of central veins, sublobular veins and, in the worst case, of liver veins. Fibri-nolysis may have a positive effect on the outcome of this disease, and single cases of an emergency implantation of a transjugular portosystemic shunt (TIPS) have been reported.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> A final option for preventing the fatal outcome would be liver transplantation.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>Differential Diagnosis of Elevated Liver EnzymesDifferential diagnosis of elevated liver enzymes under chemotherapy has to include toxic effects from the tumor itself, resulting i.e. from hepatic me-tastases, tumor-induced portal vein thrombosis, pa-raneoplastic syndromes, infiltration with amyloid or light chain deposits or pre-existing liver disease, and furthermore effects from co-medication and infectio-ns.<a class="elsevierStyleCrossRef" href="#bib0105">21</a>Causality assessment is necessary to determine the probability that liver injury is drug-induced. It includes the following steps:<a class="elsevierStyleCrossRef" href="#bib0065">13</a>,<a class="elsevierStyleCrossRef" href="#bib0070">14</a><ul class="elsevierStyleList" id="li0005"><li class="elsevierStyleListItem" id="list0005">•Latency of liver-enzyme elevation following the administration of the drug.</li><li class="elsevierStyleListItem" id="list0010">•Rate of resolution after dechallenge.</li><li class="elsevierStyleListItem" id="list0015">•Risk factors for the development of liver disease (age, alcohol, pregnancy).</li><li class="elsevierStyleListItem" id="list0020">•Exclusion of other causes (viral hepatitis, ischemia, biliary tract disease, alcohol).</li><li class="elsevierStyleListItem" id="list0025">•Concomitant drugs.</li><li class="elsevierStyleListItem" id="list0030">•Track record of the patient’s charts/of similar cases.</li><li class="elsevierStyleListItem" id="list0035">•Rechallenge with the drug (in certain cases).</li></ul>Genetic Predisposition and Drug-Metabolizing EnzymesThe degradation and detoxification of many che-motherapeutics in the liver depends on the activity of a particular enzyme pathway that may be altered by hepatocellular dysfunction induced by the drug itself.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Moreover, genetic variations or inhibition of degrading enzymes by non-cytotoxic drugs may delay hepatic metabolization of the cytotoxic agent, thus increasing its toxicity.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> A contrary effect may be observed if the cytotoxic agent is in need of activation by a hepatic enzyme (pro-drugs), or if a drug-interaction increases the expression of a hepatic enzyme (<a class="elsevierStyleCrossRef" href="#t0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Impaired detoxification may be accompanied by disturbed biliary excretion of hepa-tocytes due to a chemotherapy-included slow-down of a the hepatocellular metabolism-inducing ele-vation of serum parameters of cholestasis.<elsevierMultimedia ident="t0010"></elsevierMultimedia>Furthermore, enzyme polymorphisms of drug-metabolizing enzymes have to be taken into account, such as thiopurine S-methyltransferases (TMPT), di-hydropyrimidine dehydrogenase (DPD), aldehyde de-hydrogenases (ALDH), glutathione S-transferases (GST), uridine diphosphate glucuronosyltransferases (UGTs) and cytochrome P450 (CYP 450) enzymes.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>It has been shown, that genetic variants in the UDP-glucuronosyltransferase 1A1 predict the severe risk of neutropenia with irinotecan treatment.<a class="elsevierStyleCrossRefs" href="#bib0130">26</a>–<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Lack of DPD results in severe 5-fluorouracil induced toxicity.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>For completion, some tumors are able to overex-press multidrug-resistance genes, resulting in poor responses of the tumor to chemotherapy.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>As a result evaluation of enzyme-polymorphisms as well as of drug-plasma levels is currently gaining increased importance for the improvement of indivi-dualized therapy.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>,<a class="elsevierStyleCrossRef" href="#bib0160">32</a>Liver Disease With Therapy Regimen Used for Gastrointestinal TumorsIn case of chemotherapy-induced hepatotoxicity, dose adjustment or change of the drug-combination may become necessary (<a class="elsevierStyleCrossRef" href="#t0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0165">33</a>–<a class="elsevierStyleCrossRef" href="#bib0175">35</a><elsevierMultimedia ident="t0015"></elsevierMultimedia>Drugs can be devided into dose-dependent or predictable hepatotoxins, and dose-independent or unpredictable hepatotoxins. Dose-dependent hepato-toxins generally require metabolic activation to a toxic metabolite and interfere with subcellular orga-nelles and biochemical processes at key sites such as mitochondria or canalicular bile secretion.<a class="elsevierStyleCrossRefs" href="#bib0040">8</a>,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Liver injury produced by dose-dependent hepatotoxins usually occurs after a short latent period (hours), and is characterized by zonal necrosis or microvesi-cular steatosis (i.e. aflatoxins).<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Most clinically overt adverse hepatic events associated with drugs are unpredictable. These events can be divided into apparent hypersensitivi-ty reactions associated with fever, rash, eosino-philia, and a rapid response upon rechallenge, versus presumed metabolic unpredictable (idiosyncratic) reactions.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>5-Fluorouracil (5-FU)5-FU is the base of most combination therapies of gastrointestinal tumors. It is an uracil analogue and antimetabolite that is metabolized mainly in the liver by dihydropyrimidindehydrogenase (DPD). In case of DPD-deficiency myelotoxicity and diarrhea are the most common toxic effects, followed by mu-cositis, hand-foot-syndrome and neurotoxicity.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> 5-FU has been associated with hepatic steatosis on histological and radiological findings, but has not been shown to affect morbidity or mortality.<a class="elsevierStyleCrossRefs" href="#bib0195">39</a>–<a class="elsevierStyleCrossRef" href="#bib0205">41</a> 5-FU is fairly safe to use in patients with liver dysfunction, although regular monitoring of liver tests is advised.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>Cαpecitαbine is an oral prodrug that is converted to fluorouracil in three enzymatic steps via carboxylesterase to 5’-Desoxy-5-Fluorocytidin (5’-DFCR), cytidin-deaminase to 5’-Desoxy-5-Fluorouri-din (5’-DFUR) and by thymidine phosphorylase (TP) to the active component 5-FU. TP is an enzyme which is present at higher levels in some tumors and the liver than in other healthy tissue.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> Hyperbilirubi-naemia is common and usually reversible.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> It might be related to haemolysis.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>OxaliplatinOxaliplatin is a platinum analogue which ist given in combination with 5-FU. It belongs to the alkylating chemotherapy agents which, like Cis-or Carboplatin, result in the formation of crosslinks within and between DNA strands. Oxaliplatin is mainly excreted through the kidneys and does not undergo cytochrome P450 metabolism within the liver. Hence it is tolerated by patients with liver dys-function.<a class="elsevierStyleCrossRef" href="#bib0235">47</a> Nevertheless, studies of patients undergoing liver metastasectomy after neoadjuvant oxaliplatin-based treatment have shown histological evidence of liver damage.<a class="elsevierStyleCrossRefs" href="#bib0240">48</a>–<a class="elsevierStyleCrossRef" href="#bib0255">51</a> Neoadjuvant chemotherapy with 5-FU and oxaliplatin-based regimes has been associated with vascular changes in heal-thy liver parenchyma, more than steatosis. Frequency of oxaliplatin-associated sinusoidal obstruction or dilatation syndrome varies in reports from 20–80%,<a class="elsevierStyleCrossRefs" href="#bib0245">49</a>–<a class="elsevierStyleCrossRef" href="#bib0255">51</a> a condition which might increase morbidity but not mortality after liver metastec-tomy. Current recommendations are to limit the number of preoperative cycles if possible.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>IrinotecanIrinotecan (CPT-II) is the other main combination partner of 5-FU in advanced colorectal carcinoma therapy. It is a camptothecin analogue, and is a prodrug which requires bioactivation in the liver by carboxyesterase to form the active and lipophilic metabolite SN-38. SN-38 acts as a topoisomerase I poison and is approximately 100–1000-fold more cytotoxic than the parent drug.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Topoisomerases are enzymes which are responsible for the maintenance of DNA-topology during the S-phase. Irinote-can and its active metabolite SN-38 form a complex with topoisomerase I and inhibit DNA-replication. A similar substance is topotecan. Etoposid inhibits DNA-Topoisomerase II.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of irinotecan also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile cana-licular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on inter-individual variability.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>Toxic levels of irinotecan can accumulate from standard doses if glucuronidation is reduced, as occurs in Gilbert’s-Meulengracht syndrome.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Elevated bilirubin and AP levels are associated with decreased irinotecan clearance.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Irinotecan is associated with hepatic steatosis and steatohepatitis in up to 50% of liver-resection samples.<a class="elsevierStyleCrossRefs" href="#bib0245">49</a>–<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Steatohepatitis has been associated with increased morbidity, and increased mortality in some series, after liver resection.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>It is generally more common to use oxaliplatin-based regimens than those that are irinotecan-based for neoadjuvant treatment before liver resection.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Irinotecan can also cause mild elevations of serum transaminases and bilirubin in up to 25% of pa-tients.<a class="elsevierStyleCrossRef" href="#bib0285">57</a>GemcitabineGemcitabine (2’,2’-Difluordesoxycytidin) is a pyri-midine/deoxycytidine analogue which acts as anti-metabolite. It is a pro-drug that, once transported into the cell, undergoes intracellular phosphoryla-tion and activation by deoxycytidine kinase. Both gemcitabine diphosphate and gemcitabine triphos-phate inhibit processes required for DNA synthesis. Incorporation of gemcitabine triphosphate (dFdC-TP) into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of the gemcitabine nucleotide on the end of the elongating DNA strand, one deoxynucleotide is added and DNA polymerases are unable to proceed, a process called masked termination.<a class="elsevierStyleCrossRef" href="#bib0290">58</a>Active gemcitabine triphosphate is degraded by cytidine deaminase in liver, blood and kidney to form an inactive metabolite: 2’,2’-difluorodeoxyuri-dine (dFdU).<a class="elsevierStyleCrossRef" href="#bib0295">59</a> It is eliminated by the kidney.Administration of gemcitabine is associated with a mild rise in transaminases in up to 60% of patients, and in serum bilirubin in a small proportion of patients. These changes are usually transient, but are very rarely associated with severe hepatotoxici-ty. <a class="elsevierStyleCrossRef" href="#bib0300">60</a>,<a class="elsevierStyleCrossRef" href="#bib0305">61</a> Monitoring of liver tests in patients who are receiving gemcitabine is recommended, the expected mild rise in transaminases is usually of no clinical consequence.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> In case of slightly elevated transami-nases, gemcitabine is generally well tolerated without increased toxicity. However, in patients with primarily elevated bilirubin, significant deterioration in liver function under therapy has been described. Patients with elevated creatinine levels had significant toxicity even at reduced doses.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>DacarbacineDacarbazine is an alkylating agent and crosslinks DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. It is used in the therapy of advanced neuroendocrine tumors, malignant melanoma, hodgkins lymphoma and sarcoma. Common side-effects include nausea and vomiting and bone-marrow suppression. There are case reports which indicate that next to elevation of liver enzymes, there might be hepatic veno-oclusive disease associated with the administration of Dacarbazine.<a class="elsevierStyleCrossRef" href="#bib0315">63</a>ImatinibImatinib is an oral small-molecule tyrosine kina-se inhibitor, effective to inhibit the BCR-ABL kinase in chronic myeloid leukaemia and the KIT tyrosine kinase and platelet-derived growth factor receptor in gastrointestinal stromal tumors (GISTs). Cases of severe liver injury are rare. In the two large multicentre studies with 147 and 946 patients treated for GIST, abnormal liver function tests were observed in 5.4% of treated patients (including grade 3–4 toxicity in 2.7%), and fatal liver disease occurred in 3%.<a class="elsevierStyleCrossRef" href="#bib0320">64</a>,<a class="elsevierStyleCrossRef" href="#bib0325">65</a> In chronic myeloic leukemia imatinib was found to cause grade 2 or higher elevations in serum aminotransferases in 8% of the treated patients and grade 3–4 elevations in 1–5%. Grade 3–4 elevations in serum bilirubin levels were reported in 0.4–3.5% of the patients.<a class="elsevierStyleCrossRef" href="#bib0330">66</a>SorafenibSorafenib is an orally available multi-kinase inhibitor, which has shown effectivity against hepatoce-llular carcinoma and renal-cell carcinoma. It is mainly metabolized in the liver through both, an oxidative pathway mediated by cytochrome P450 and UGT 1A9-mediated glucuronidation; excretion is mostly faecally.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> A phase I study of sorafenib in patients with liver dysfunction who were devided into groups on the basis of bilirubin levels, albumin levels, and renal function, showed that although drug clearance did not differ between groups, dose-limiting toxic effects occurred with increasing biliru-bin levels and decreased albumin.<a class="elsevierStyleCrossRef" href="#bib0335">67</a>Cetuximab and panitumumabThe epidermal growth factor receptor (EGFR) is a member of the ErbB family of closely related tyrosine kinase receptors: EGFR (ErbB-l/HER-1), ErbB-2 (HER-2/neu), ErbB-3 (HER-3), and ErbB-4 (HER-4). Cetuximab and panitumumab are monoclonal antibodies that block the ligand binding site of the EGFR, thus inhibiting intracellular signaling. Cetuximab is a chimeric human-mouse antibody, while panitumu-mab is a fully humanized monoclonal anti-EGFR an-tibody. Common side effects of these antibodies include acneiform rash, diarrhea, and hypomagnesemia and hypersensitivity reactions that can be particularly severe with the chimeric antibody.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> Recent retrospective analyses from several large trials show that patients with tumors bearing the KRAS mutation do not respond to either cetuximab-or panitumumab-ba-sed therapy.<a class="elsevierStyleCrossRefs" href="#bib0345">69</a>–<a class="elsevierStyleCrossRef" href="#bib0355">71</a> These antibodies are generally used in combination with 5-FU based therapy. However there are positive results for monotherapy in advanced disease. In a case of chronic cholestasis and hy-perbilirubinemia caused by advanced liver involvement which prohibits second-line treatment, combined antibody treatment with cetuximab and be-vacizumab (an antibody against vascular endothelial growth factor) was given and well-tolerated. Clinical performance status as well as laboratory parameters improved rapidly and combined chemotherapy could be administered.<a class="elsevierStyleCrossRef" href="#bib0360">72</a>BevacizumabBevacizumab is a humanized antibody targeting vascular endothelial growth factor A (VEGF-A).<a class="elsevierStyleCrossRef" href="#bib0340">68</a> It has been approved in first-and second-line treat-ment of metastatic colorectal cancer in combination with 5-FU and in lung cancer in combination with carboplatin and paclitaxel. It has also shown benefit in metastatic breast cancer when combined with pa-clitaxel.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> The relatively well-known side effects include hypertension, gastrointestinal perforation, arterial thromboembolic events and postoperative bleeding or wound-healing complications. Treatment with this antibody is safe, even with elevated liver values. Bevacizumab has no impact on hepatic stea-tosis and fibrosis.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> As for sinusoidal obstructions, results are contradictory. One report states that be-vacizumab protects against the sinusoidal obstruction syndrome,<a class="elsevierStyleCrossRef" href="#bib0370">74</a> whilst there are case reports of hepatic injury including veno-occlusive disease<a class="elsevierStyleCrossRef" href="#bib0375">75</a> and singular lesions with necrotic liver parenchyma with inflammatory reaction.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> The reported side-effects however resolved after cessation of the thera-py.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> Even though these reactions are rare and unusual, one should be aware that bevacizumab might cause portal hypertension with elevation of transaminases and bilirubin.Risks of Neoadjuvant ChemotherapyThe changes (steatosis, steatohepatitis, sinusoidal injury) described above may be responsible for complications after surgery when neoadjuvant chemotherapy is performed in patients with advanced cancer. The preoperative chemotherapy however has several advantages: 1) it downsizes tumors, 2) it increases curative resection rates and 3) it converts some patients from having unresectable to resectable disease. This kind of therapy has been however associated with an increased risk of perioperative morbidity or 90 days mortality.<a class="elsevierStyleCrossRef" href="#bib0380">76</a>,<a class="elsevierStyleCrossRef" href="#bib0385">77</a> In general, there is no increase in complications even in the presence of severe (> 30%) steatosis, when steatohepatitis (stea-tosis with inflammation) is excluded.<a class="elsevierStyleCrossRef" href="#bib0390">78</a>Hepatic steatosis, a mild manifestation of non-alcoholic fatty liver disease (NAFLD), may occur after treatment with 5-FU.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> Steatohepatitis is for instance associated with irinotecan therapy. Hepatic sinusoidal obstruction can occur with oxaliplatin treatment and appears to increase in severity with prolonged treatment (> 6 cycles). It does however not appear to be associated with an increased risk of perioperative death.<a class="elsevierStyleCrossRefs" href="#bib0205">41</a>,<a class="elsevierStyleCrossRef" href="#bib0390">78</a> Bevacizumab can be used safely when discontinued > 5 weeks before liver re-section.<a class="elsevierStyleCrossRef" href="#bib0395">79</a>Future AspectsCancer continues to be one of the major causes of mortality throughout the world. Modern combination chemotherapy allows for a longer time-to-progression (TTP) and longer overall survival (OS) even in advanced disease - resulting in a prolonged treatment. Longer treatment times lead to increased toxic effects, especially in an aging patient collective. Whilst the maximal tolerable dose (MTD) might be given at the beginning of a therapy and particularly in the neoadjuvant and adjuvant treatment settings, it might not be possible to continue this treatment over a longer period, especially in palliative treatment.Therefore, we should ask ourselves, what would be the minimal effective dose (MED) to treat our long-term patients, and when to change. Whilst prognostic biomarkers help to give us information about the therapeutic outcome of a specific disease, predictive biomarkers might help us to anticipate the effect of a specific therapy for this disease whilst keeping the side effects tolerable.Accounting for further individual parameters of the patients such as age, gender and disease stage, matched to the expected side effects under a given dose, the efficacy of a treatment as well as the quality of life of our tumor patients, shall be maintained as good as possible." "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres1217525" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1132906" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "The Liver is the Central Organ of Intermediate Metabolism and is Crucial in Host Defense" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Basic Principles of Cytotoxic Chemotherapy" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "The Liver May Become A “Target” of and May Suffer From Cytotoxic Chemotherapy" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Impact of Cytotoxic Chemotherapy on Liver Function: Hepatocellular Dysfunction and Clinical Implications" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Impairment of Liver Function During Cytotoxic Chemotherapy: Impact on Clearance Function" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Drug-Induced Liver Disease" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Veno-Occlusive Disease of the Liver" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Differential Diagnosis of Elevated Liver Enzymes" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Genetic Predisposition and Drug-Metabolizing Enzymes" ] 11 => array:3 [ "identificador" => "sec0050" "titulo" => "Liver Disease With Therapy Regimen Used for Gastrointestinal Tumors" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "5-Fluorouracil (5-FU)" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Oxaliplatin" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Irinotecan" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Gemcitabine" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "Dacarbacine" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Imatinib" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "Sorafenib" ] 7 => array:2 [ "identificador" => "sec0090" "titulo" => "Cetuximab and panitumumab" ] 8 => array:2 [ "identificador" => "sec0095" "titulo" => "Bevacizumab" ] ] ] 12 => array:2 [ "identificador" => "sec0100" "titulo" => "Risks of Neoadjuvant Chemotherapy" ] 13 => array:2 [ "identificador" => "sec0105" "titulo" => "Future Aspects" ] 14 => array:1 [ "titulo" => "Reference" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1132906" "palabras" => array:4 [ 0 => "Chemotherapy" 1 => "Liver" 2 => "Side effects" 3 => "Host defence" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The liver is the largest parenchymatous organ of the body and central for intermediate metabolism. Its close contact to the portal blood streaming back from the gut and the systemic circulation is a prerequisite for the various processes ongoing on cellular level. The spatial relationship of the hepatocytes with the different cellular structures of the liver, such as fenestrated sinusoidal endothelial cells, Kupffer cells, and bile canaliculi is important for the organization and performance of the intermediate metabolism of nutrients (proteins, glucose and fatty acids), for the clearance of toxic or infectious agents, for metabolic detoxification and for the excretion of waste products.The administration of chemotherapy is a challenge for the tight regulation and balance of these processes. As most drugs tend to be lipophilic, they are readily taken up by the liver. Under chemotherapy, up to 85% of patients develop liver steatosis. Steatohepatitis is the more serious event, especially if accompanied by an increase in bilirubin levels.Modern understanding of the efficacy, safety and tolerability of combination chemotherapy has to increasingly include the individual context of a patient, such as age, gender, nutritional status, underlying diseases, genetic predisposition, as well as the cross-reactivity of the different drugs.This review tries to capture the various effects of chemotherapy on the liver, with a focus on chemothe-rapeutical compounds used for the treatment of gastrointestinal cancers." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 564 "Ancho" => 997 "Tamanyo" => 62033 ] ] "descripcion" => array:1 [ "en" => "A 62 years old patient with the first diagnosis of a cholangiocarcinoma in June 2006. The MRCP (A) showed a strong intrahepatic cholestasis with high bilirubin levels (E). Therefore a PTC was performed. The PTC (B) showed a dilation of the intrahepatic bile ducts and a subtotal stenosis of the DHC. In a “Rendezvous-technique” (PTC together with ERCP; C) it was possible to pass the DHC stenosis and place one stent in the right and one stent in the left main bile duct (D). The bilirubin levels decreased and a chemotherapy with gemcitabine was started. Actually the patient has further on normal bilirubin levels (E)." ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 655 "Ancho" => 997 "Tamanyo" => 199505 ] ] "descripcion" => array:1 [ "en" => "Liver-steαtosis induced by chemotherapy, H&E staining." ] ] 2 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table I" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "+++ very often. ++ often. + rare. (+) very rare. 0 no hepato-toxicity" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Hepatotoxicity \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Asparaginase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Carmustine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Mercatopurin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">++ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Capecitabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Chlorambucil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cyclophosphamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cytarabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dacarbazine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Doxorubicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Etoposide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Gemcitabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Mitomycin C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Streptozocin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Busulfan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cisplatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">5-FU \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Irinotecan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Imatinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Oxaliplatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Vincristine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(+) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Bevacizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cetuximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Epirubicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Hydroxyurea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rituximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">0 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078569.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Hepatotoxicity of cytotoxic chemotherapeutics." ] ] 3 => array:7 [ "identificador" => "t0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "d: downregulation. u: upregulation of the enzyme by the agent" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Drug metabolizing enzymes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Interaction \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cytochrome P450 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">CYP2B6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cyclophosphamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">CYP2C8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Paclitaxel \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">CYP3A4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Etoposide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Ketoconazole (d) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Vinca alkaloids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Erythromycin (d) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Ifosfamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Grapefruit joice (d) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Docetaxel \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Corticosteroids (u) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Irinotecan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Phenytoin (u) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Ketoreductase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Anthracyclines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Carboxylesterases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Irinotecan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dihydropyrimidine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">5-Fluorouracil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dehydrogenase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078568.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Liver chemotherapeutics-metabolizing enzymes and interaction with drugs." ] ] 4 => array:7 [ "identificador" => "t0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Table modified after.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>,<a class="elsevierStyleCrossRef" href="#bib0175">35</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "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"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Drug name \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Liver toxic effects \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Frequency \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Severity \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Dose modification \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="middle" scope="col">Reference \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Fluorouracil (5-FU) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Steatosis Hepatoxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Subclinical Usually Subclinical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">No dose adjustment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0195">39</a>-<a class="elsevierStyleCrossRef" href="#bib0200">40</a>,<a class="elsevierStyleCrossRef" href="#bib0210">42</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Oxaliplatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Vascular changes: Sinusoidal obstruction or dilatation Syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common (20–80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Might increase morbidity, but not mortality after liver Resection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">No dose adjustment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0235">47</a>,<a class="elsevierStyleCrossRefs" href="#bib0245">49</a>-<a class="elsevierStyleCrossRef" href="#bib0255">51</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Increased bilirubin. AST or AP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">No effect on drug clearance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Irinotecan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Steatosis and steatohepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common (25–50%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Steatohepatitis can Increase morbidity If used before liver Resection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Increased AST alone no increase of toxic effects increase of Bilirubin: \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0195">39</a>,<a class="elsevierStyleCrossRef" href="#bib0245">49</a>,<a class="elsevierStyleCrossRef" href="#bib0255">51</a>,<a class="elsevierStyleCrossRef" href="#bib0275">55</a>-<a class="elsevierStyleCrossRef" href="#bib0280">56</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Increased aminotransferases and bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Up to 25% of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Usually reversible \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Neutropenia and diarrhea, dose reduction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Capecitabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Hyperbilirubinaemia, usually without increased AP and γGT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common (23–25%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Grad 3–4 in up to 23% of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">No dose adjustmen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRefs" href="#bib0220">44</a>-<a class="elsevierStyleCrossRef" href="#bib0230">46</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Cisplatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">increased aminotransferases \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common (with high doses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Usually transient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Unlikely to need dose adjustment, \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0405">81</a>-<a class="elsevierStyleCrossRef" href="#bib0410">82</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Steatosis and cholectasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Usually transient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">mainly renal excretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dacarbazine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Case report of fulminate liver failure (thrombotic occlusions) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Can be life threatening \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0315">63</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Doxorubicin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Idiosyncratic reactions, including increased aminotransferases and bilirubin (myelosuppression, mucositis) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Usually transient \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dose adjustment with elevated bilirubin levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0410">82</a>,<a class="elsevierStyleCrossRef" href="#bib0415">83</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Etoposide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">In pre-existing liver disease: Mild to moderate impairment: no pharmacokinetic effect, Severe impairment: myelosuppression, mucositis. Decreased albumin increases unbound drug concentration and increases haematological toxic effects Veno-occlusive disease in higher doses Case reports of severe hepatocellular damage at standard doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Common in bone-marrow transplant-tation (10–25%) Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Severe and life-threatening Severe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Unclear (increase renal crearance might compensate) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRefs" href="#bib0420">84</a>-<a class="elsevierStyleCrossRef" href="#bib0430">86</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Gemcitabine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Increased aminotransferases Increased bilirubin Case reports of fatal cholestatic hepatotoxicity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Veri common (up To 60%) Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Generally transient and reversible Deterioration of Liver function Can be fatal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">No dose adjustment Reduce dose (20%) and increased if tolerated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRefs" href="#bib0300">60</a>-<a class="elsevierStyleCrossRef" href="#bib0310">62</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Imatinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Increased aminotransferases or bilirubin Liver necrosis of failure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">5–8% Rare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">2–8% grade 3–4 Case reports of Fatalities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Stop treatment if hepatotoxicity develops, should probably not Rechallenge \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRefs" href="#bib0320">64</a>-<a class="elsevierStyleCrossRef" href="#bib0330">66</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Sorafenib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">In pre-existing liver disease: clearance does not differ between patient cohorts \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">Dose adjustment with elevated bilirubin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="middle">(<a class="elsevierStyleCrossRef" href="#bib0335">67</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078567.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Chemotherapeutic agents and associated toxic liver effects. Table modified after.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>,<a class="elsevierStyleCrossRef" href="#bib0175">35</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "Reference" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:86 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Developmental anatomy and normal structure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "MacSween R.N.M." 1 => "Desmet V.J." 2 => "Roskams T." 3 => "Scothorne R.J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:4 [ "editores" => "MacSweenR.N.M., BurtA.D., PortmannB.C." "titulo" => "Pathology of the liver" "paginaInicial" => "1" "serieFecha" => "2002" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Roy-Chowdhury N, Roy-Chowdhury J. Liver Physiology and Energy Metabolism. In: Feldman M, Friedman LS, Brandt LJ (eds.). Gastrointestinal and Liver Disease. 2nd. Ed. Philadelphia; 2006, p. 1551." ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver endocytosis and Kupffer cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Toth C.A." 1 => "Thomas P." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:8 [ "tituloSerie" => "Hepatology" "fecha" => "1992" "volumen" => "16" "numero" => "1" "paginaInicial" => "255" "paginaFinal" => "266" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1319954" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0302283812007087" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Functional spectrum of sinusoidal endothelial liver cells. Filtration, endocytosis, synthetic capacities and intercellular communication" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Rieder H." 1 => "Meyer zum Buschenfelde K.H." 2 => "Ramadori G." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Hepatol" "fecha" => "1992" "volumen" => "15" "numero" => "1-2" "paginaInicial" => "237" "paginaFinal" => "250" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1506642" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cytotoxic drugs, programmed cell death, and the immune system: defining new roles in an old play" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Debatin K.M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jnci/89.11.750" "Revista" => array:7 [ "tituloSerie" => "J Natl Cancer Inst" "fecha" => "1997" "volumen" => "89" "numero" => "11" "paginaInicial" => "750" "paginaFinal" => "751" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9182966" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An alteration in the nuclei of rat liver cells in starvation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Parr L." 1 => "Mossberg S.M." 2 => "Rosenzweig M.W." 3 => "Breslar E.I." 4 => "Clark G." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "edicion" => "116th. Ed." "fecha" => "2005" "paginaInicial" => "457" "paginaFinal" => "468" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of malnutrition on regeneration and composition of the liver in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Skullman S." 1 => "Ihse I." 2 => "Larsson J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Acta Chir Scand" "fecha" => "1990" "volumen" => "156" "numero" => "10" "paginaInicial" => "717" "paginaFinal" => "722" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2264430" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver Disease Caused by Drugs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Teoh N.C." 1 => "Farrell G.C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:5 [ "editores" => "FledmanM., FriedmanL.S., BrandtL.J." "titulo" => "Gastrointestinal and Liver Disease" "paginaInicial" => "1807" "edicion" => "2nd. Ed." "serieFecha" => "2006" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell biology and kinetics of Kupffer cells in the liver" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Wake K." 1 => "Decker K." 2 => "Kirn A." 3 => "Knook D.L." 4 => "McCuskey R.S." 5 => "Bouwens L." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Int Rev Cytol" "fecha" => "1989" "volumen" => "118" "paginaInicial" => "173" "paginaFinal" => "229" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2691426" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0090429510017760" "estado" => "S300" "issn" => "00904295" ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Functional characterization of two different Kupffer cell populations of normal rat liver" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Armbrust T." 1 => "Ramadori G." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Hepatol" "fecha" => "1996" "volumen" => "25" "numero" => "4" "paginaInicial" => "518" "paginaFinal" => "528" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8912152" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mononuclear phagocytes of acutely injured rat liver abundantly synthesize and secrete fibronectin in contrast to Kupffer cells of normal liver" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Armbrust T." 1 => "Ramadori G." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/bbrc.1995.2194" "Revista" => array:8 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "1995" "volumen" => "213" "numero" => "3" "paginaInicial" => "752" "paginaFinal" => "758" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7654234" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0022534714001979" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alteration of rat Kupffer cell function following mitomycin-C administration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Bodenheimer H. Jr." 1 => "Charland C." 2 => "Leith J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jlb.43.3.265" "Revista" => array:8 [ "tituloSerie" => "J Leukoc Biol" "fecha" => "1988" "volumen" => "43" "numero" => "3" "paginaInicial" => "265" "paginaFinal" => "270" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3125296" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0302283816302007" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Causality assessment versus guilt-by-association in drug hepatotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Kaplowitz N." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2001.21083" "Revista" => array:7 [ "tituloSerie" => "Hepatology" "fecha" => "2001" "volumen" => "33" "numero" => "1" "paginaInicial" => "308" "paginaFinal" => "310" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11124850" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of two clinical scales for causality assessment in hepatotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Lucena M.I." 1 => "Camargo R." 2 => "Andrade R.J." 3 => "Perez-Sanchez C.J." 4 => "Sanchez D.L.C." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2001.20645" "Revista" => array:7 [ "tituloSerie" => "Hepatology" "fecha" => "2001" "volumen" => "33" "numero" => "1" "paginaInicial" => "123" "paginaFinal" => "130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11124828" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug induced liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Kaplowitz N." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "fecha" => "2007" "paginaInicial" => "1" "editorial" => "Informa Health Care" "editorialLocalizacion" => "NY" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer Chemotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "DeLeve L.D." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "KaplowitzN., DeLeveL.D." "titulo" => "Drug-induced liver disease" "paginaInicial" => "631" "paginaFinal" => "662" "edicion" => "2nd. Ed." "serieFecha" => "2007" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Veno-occlusive disease of the liver" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Bearman S.I." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Curr Opin Oncol" "fecha" => "2000" "volumen" => "12" "numero" => "2" "paginaInicial" => "103" "paginaFinal" => "109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10750719" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (venoocclusive disease)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "DeLeve L.D." 1 => "Shulman H.M." 2 => "McDonald G.B." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2002-23204" "Revista" => array:7 [ "tituloSerie" => "Semin Liver Dis" "fecha" => "2002" "volumen" => "22" "numero" => "1" "paginaInicial" => "27" "paginaFinal" => "42" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11928077" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful treatment of hepatic veno-occlusive disease in a peripheral blood progenitor cell transplant patient with a transjugular intrahepatic portosystemic stent-shunt (TIPS)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "de la Rubia J." 1 => "Carral A." 2 => "Montes H." 3 => "Urquijo J.J." 4 => "Sanz G.F." 5 => "Sanz M.A." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Haematologica" "fecha" => "1996" "volumen" => "81" "numero" => "6" "paginaInicial" => "536" "paginaFinal" => "539" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9009442" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Orthotopic liver transplantation for venoocclusive disease complicating autologous bone marrow transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Norris S." 1 => "Crosbie O." 2 => "McEntee G." 3 => "Traynor O." 4 => "Nolan N." 5 => "McCann S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Transplantation" "fecha" => "1997" "volumen" => "63" "numero" => "10" "paginaInicial" => "1521" "paginaFinal" => "1524" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9175821" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatotoxicity of chemotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Floyd J." 1 => "Mirza I." 2 => "Sachs B." 3 => "Perry M.C." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.seminoncol.2005.11.002" "Revista" => array:7 [ "tituloSerie" => "Semin Oncol" "fecha" => "2006" "volumen" => "33" "numero" => "1" "paginaInicial" => "50" "paginaFinal" => "67" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16473644" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human drug metabolism in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Sitar D.S." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Pharmacol Ther" "fecha" => "1989" "volumen" => "43" "numero" => "3" "paginaInicial" => "363" "paginaFinal" => "375" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2682685" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Drug metabolism polymorphisms as modulators of cancer susceptibility" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Taningher M." 1 => "Malacarne D." 2 => "Izzotti A." 3 => "Ugolini D." 4 => "Parodi S." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s1383-5742(99)00005-8" "Revista" => array:7 [ "tituloSerie" => "Mutat Res" "fecha" => "1999" "volumen" => "436" "numero" => "3" "paginaInicial" => "227" "paginaFinal" => "261" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10354524" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of pro-drug therapy in the treatment of cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Ferguson M.J." 1 => "Ahmed F.Y." 2 => "Cassidy J." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1054/drup.2001.0207" "Revista" => array:8 [ "tituloSerie" => "Drug Resist Updat" "fecha" => "2001" "volumen" => "4" "numero" => "4" "paginaInicial" => "225" "paginaFinal" => "232" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11991677" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0022534713051392" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacogenetics and cancer chemotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Iyer L." 1 => "Ratain M.J." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Eur J Cancer" "fecha" => "1998" "volumen" => "34" "numero" => "10" "paginaInicial" => "1493" "paginaFinal" => "1499" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9893619" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Ando Y." 1 => "Ueoka H." 2 => "Sugiyama T." 3 => "Ichiki M." 4 => "Shimokata K." 5 => "Hasegawa Y." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Ther Drug Monit" "fecha" => "2002" "volumen" => "24" "numero" => "1" "paginaInicial" => "111" "paginaFinal" => "116" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11805731" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Irinotecan pharmacogenetics: influence of pharmacodynamic genes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Hoskins J.M." 1 => "Marcuello E." 2 => "Altes A." 3 => "Marsh S." 4 => "Maxwell T." …1 ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/1078-0432.CCR-07-1472" "Revista" => array:8 [ "tituloSerie" => "Clin Cancer Res" "fecha" => "2008" "volumen" => "14" "numero" => "6" "paginaInicial" => "1788" "paginaFinal" => "1796" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022346817305407" "estado" => "S300" "issn" => "00223468" ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2004.07.173" "Revista" => array:8 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2004" "volumen" => "22" "numero" => "8" "paginaInicial" => "1382" "paginaFinal" => "1388" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S1078143913001129" "estado" => "S300" "issn" => "10781439" ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Cancer Res" "fecha" => "1999" "volumen" => "5" "numero" => "10" "paginaInicial" => "2672" "paginaFinal" => "2673" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MDR1 (multidrug resistance) gene expression in human primary liver cancer and cirrhosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "J Hepatol" "fecha" => "1993" "volumen" => "18" "numero" => "2" "paginaInicial" => "168" "paginaFinal" => "172" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2007.13.3934" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2008" "volumen" => "26" "numero" => "13" "paginaInicial" => "2099" "paginaFinal" => "2105" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32." "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Yoo C. A cross-sectional study of imatinib serum levels in patients with advanced GIST. Abstract 161 ed. 2010." ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemotherapy dosing in the setting of liver dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Oncology (Williston Park)" "fecha" => "2005" "volumen" => "19" "numero" => "8" "paginaInicial" => "1057" "paginaFinal" => "1063" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Part II: Liver function in oncology: towards safer chemotherapy use" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(08)70307-3" "Revista" => array:8 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2008" "volumen" => "9" "numero" => "12" "paginaInicial" => "1181" "paginaFinal" => "1190" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0302283814001651" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Part I: Liver function in oncology: biochemistry and beyond" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(08)70279-1" "Revista" => array:7 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2008" "volumen" => "9" "numero" => "11" "paginaInicial" => "1092" "paginaFinal" => "1101" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular pathogenesis of cholestasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM199810223391707" "Revista" => array:8 [ "tituloSerie" => "N Engl J Med" "fecha" => "1998" "volumen" => "339" "numero" => "17" "paginaInicial" => "1217" "paginaFinal" => "1227" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022534709005412" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Histopathology of drug-induced liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "KaplowitzN., DeLeveL.D." "titulo" => "Drug-induced liver disease" "paginaInicial" => "237" "paginaFinal" => "289" "edicion" => "2nd edition ed." "serieFecha" => "2007" ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00280-009-1147-x" "Revista" => array:7 [ "tituloSerie" => "Cancer Chemother Pharmacol" "fecha" => "2010" "volumen" => "65" "numero" => "2" "paginaInicial" => "403" "paginaFinal" => "406" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.1993.11.12.2386" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "1993" "volumen" => "11" "numero" => "12" "paginaInicial" => "2386" "paginaFinal" => "2390" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/bjc.1998.333" "Revista" => array:7 [ "tituloSerie" => "Br J Cancer" "fecha" => "1998" "volumen" => "77" "numero" => "11" "paginaInicial" => "2008" "paginaFinal" => "2011" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/bjs.5719" "Revista" => array:8 [ "tituloSerie" => "Br J Surg" "fecha" => "2007" "volumen" => "94" "numero" => "3" "paginaInicial" => "274" "paginaFinal" => "286" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0302283808008609" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdg302" "Revista" => array:7 [ "tituloSerie" => "Ann Oncol" "fecha" => "2003" "volumen" => "14" "numero" => "7" "paginaInicial" => "1142" "paginaFinal" => "1147" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s002800050043" "Revista" => array:7 [ "tituloSerie" => "Cancer Chemother Pharmacol" "fecha" => "2000" "volumen" => "45" "numero" => "4" "paginaInicial" => "291" "paginaFinal" => "297" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdg500" "Revista" => array:7 [ "tituloSerie" => "Ann Oncol" "fecha" => "2003" "volumen" => "14" "numero" => "12" "paginaInicial" => "1735" "paginaFinal" => "1743" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2001.19.21.4097" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2001" "volumen" => "19" "numero" => "21" "paginaInicial" => "4097" "paginaFinal" => "4106" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fluoropyrimidine therapy: hyperbilirubinemia as a consequence of hemolysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00280-005-1011-6" "Revista" => array:7 [ "tituloSerie" => "Cancer Chemother Pharmacol" "fecha" => "2005" "volumen" => "56" "numero" => "6" "paginaInicial" => "594" "paginaFinal" => "602" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Semin Oncol" "fecha" => "2003" "volumen" => "30" "numero" => "4 Suppl. 15" "paginaInicial" => "14" "paginaFinal" => "19" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2006.05.8156" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2006" "volumen" => "24" "numero" => "31" "paginaInicial" => "4983" "paginaFinal" => "4990" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejso.2007.07.007" "Revista" => array:7 [ "tituloSerie" => "Eur J Surg Oncol" "fecha" => "2008" "volumen" => "34" "numero" => "6" "paginaInicial" => "609" "paginaFinal" => "614" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdh095" "Revista" => array:7 [ "tituloSerie" => "Ann Oncol" "fecha" => "2004" "volumen" => "15" "numero" => "3" "paginaInicial" => "460" "paginaFinal" => "466" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2005.05.3074" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2006" "volumen" => "24" "numero" => "13" "paginaInicial" => "2065" "paginaFinal" => "2072" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lessons learned from the irinotecan metabolic pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Curr Med Chem" "fecha" => "2003" "volumen" => "10" "numero" => "1" "paginaInicial" => "41" "paginaFinal" => "49" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Etoposide: Discovery and medicinal chemistry. Current medicinal chemistry" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:6 [ "edicion" => "11th. Ed." "fecha" => "2004" "paginaInicial" => "43" "paginaFinal" => "66" "editorial" => "Bentham" "editorialLocalizacion" => "Oak Park IL" ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Cancer Res" "fecha" => "2001" "volumen" => "7" "numero" => "8" "paginaInicial" => "2182" "paginaFinal" => "2194" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2002.03.123" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2002" "volumen" => "20" "numero" => "21" "paginaInicial" => "4303" "paginaFinal" => "4312" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jamcollsurg.2005.01.024" "Revista" => array:7 [ "tituloSerie" => "J Am Coll Surg" "fecha" => "2005" "volumen" => "200" "numero" => "6" "paginaInicial" => "845" "paginaFinal" => "853" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topoisomerase I inhibitors. An overview of the camptothecin analogs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Hematol Oncol Clin North Am" "fecha" => "1994" "volumen" => "8" "numero" => "2" "paginaInicial" => "333" "paginaFinal" => "355" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gemcitabine: metabolism, mechanisms of action, and self-potentiation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Semin Oncol" "fecha" => "1995" "volumen" => "22" "numero" => "4 Suppl. 11" "paginaInicial" => "3" "paginaFinal" => "10" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of gemcitabine and 2’,2’-difluorodeoxyuridine in a patient with ascites" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:8 [ "tituloSerie" => "Pharmacotherapy" "fecha" => "2000" "volumen" => "20" "numero" => "10" "paginaInicial" => "1204" "paginaFinal" => "1207" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022534710002569" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fatal cholestatic liver failure associated with gemcitabine therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Dig Dis Sci" "fecha" => "2003" "volumen" => "48" "numero" => "9" "paginaInicial" => "1804" "paginaFinal" => "1808" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gemcitabine-induced liver fibrosis in a patient with pancreatic cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "JOP" "fecha" => "2007" "volumen" => "8" "numero" => "4" "paginaInicial" => "460" "paginaFinal" => "467" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2000.18.14.2780" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2000" "volumen" => "18" "numero" => "14" "paginaInicial" => "2780" "paginaFinal" => "2787" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic veno-occlusive disease due to DTIC" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1097-0142(19800515)45:10<2670::aid-cncr2820451031>3.0.co;2-l" "Revista" => array:7 [ "tituloSerie" => "Cancer" "fecha" => "1980" "volumen" => "45" "numero" => "10" "paginaInicial" => "2670" "paginaFinal" => "2674" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa020461" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2002" "volumen" => "347" "numero" => "7" "paginaInicial" => "472" "paginaFinal" => "480" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(04)17098-0" "Revista" => array:8 [ "tituloSerie" => "Lancet" "fecha" => "2004" "volumen" => "364" "numero" => "9440" "paginaInicial" => "1127" "paginaFinal" => "1134" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0302283814012354" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Imatinib mesylate (gleevec) hepatotoxicity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10620-006-9117-1" "Revista" => array:7 [ "tituloSerie" => "Dig Dis Sci" "fecha" => "2007" "volumen" => "52" "numero" => "2" "paginaInicial" => "598" "paginaFinal" => "601" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67." "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Miller AA, Murray DJ, Owzar K. Pharmakokinetic (PK) and phase I study of sorafenib (S) for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (HD or RD): CALGB 60301. 25, abstr. 3538 ed. 2007." ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Current progress in targeted therapy for colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/107327481001700102" "Revista" => array:7 [ "tituloSerie" => "Cancer Control" "fecha" => "2010" "volumen" => "17" "numero" => "1" "paginaInicial" => "7" "paginaFinal" => "15" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2007.14.7116" "Revista" => array:8 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2008" "volumen" => "26" "numero" => "10" "paginaInicial" => "1626" "paginaFinal" => "1634" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022534709011720" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2008.20.8397" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2009" "volumen" => "27" "numero" => "5" "paginaInicial" => "663" "paginaFinal" => "671" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2008.19.8135" "Revista" => array:8 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2009" "volumen" => "27" "numero" => "5" "paginaInicial" => "672" "paginaFinal" => "680" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S030228381201531X" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effective second-line treatment with cetuximab and bevacizumab in a patient with hepatic metastases of colorectal cancer and hyperbilirubinemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000106098" "Revista" => array:8 [ "tituloSerie" => "Onkologie" "fecha" => "2007" "volumen" => "30" "numero" => "10" "paginaInicial" => "509" "paginaFinal" => "512" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0302283812014364" "estado" => "S300" "issn" => "03022838" ] ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic injury associated with bevacizumab use in metastatic breast and colon cancers: a review of two cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Commun Oncol" "fecha" => "2008" "volumen" => "5" "paginaInicial" => "539" "paginaFinal" => "542" ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejso.2008.12.013" "Revista" => array:7 [ "tituloSerie" => "Eur J Surg Oncol" "fecha" => "2009" "volumen" => "35" "numero" => "5" "paginaInicial" => "515" "paginaFinal" => "520" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 74 => array:3 [ "identificador" => "bib0375" "etiqueta" => "75." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sinusoidal obstruction syndrome (venoocclusive disease) in a patient receiving bevacizumab for metastatic colorectal cancer: a case report" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "fecha" => "2007" "volumen" => "2" "paginaInicial" => "227" "itemHostRev" => array:3 [ "pii" => "S0022534710037791" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 75 => array:3 [ "identificador" => "bib0380" "etiqueta" => "76." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2005.03.2334" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2005" "volumen" => "23" "numero" => "36" "paginaInicial" => "9073" "paginaFinal" => "9078" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 76 => array:3 [ "identificador" => "bib0385" "etiqueta" => "77." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.sla.0000193603.26265.c3" "Revista" => array:7 [ "tituloSerie" => "Ann Surg" "fecha" => "2006" "volumen" => "243" "numero" => "1" "paginaInicial" => "1" "paginaFinal" => "7" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 77 => array:3 [ "identificador" => "bib0390" "etiqueta" => "78." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trends in long-term survival following liver resection for hepatic colorectal metastases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00000658-200206000-00002" "Revista" => array:7 [ "tituloSerie" => "Ann Surg" "fecha" => "2002" "volumen" => "235" "numero" => "6" "paginaInicial" => "759" "paginaFinal" => "766" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 78 => array:3 [ "identificador" => "bib0395" "etiqueta" => "79." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemotherapy prior to hepatic resection for colorectal liver metastases: helpful until harmful?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000184733" "Revista" => array:7 [ "tituloSerie" => "Dig Surg" "fecha" => "2008" "volumen" => "25" "numero" => "6" "paginaInicial" => "421" "paginaFinal" => "429" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 79 => array:3 [ "identificador" => "bib0400" "etiqueta" => "80." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Cancer Chemother Rep" "fecha" => "1975" "volumen" => "59" "paginaInicial" => "647" "paginaFinal" => "659" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 80 => array:3 [ "identificador" => "bib0405" "etiqueta" => "81." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemotherapy dosing in the setting of liver dysfunction" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Oncology (Williston Park)" "fecha" => "2005" "volumen" => "19" "paginaInicial" => "1057" "paginaFinal" => "1063" ] ] ] ] ] ] 81 => array:3 [ "identificador" => "bib0410" "etiqueta" => "82." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic injury during doxorubicin therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Pathol Lab Med" "fecha" => "1984" "volumen" => "108" "paginaInicial" => "912" "paginaFinal" => "913" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 82 => array:3 [ "identificador" => "bib0415" "etiqueta" => "83." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetics of anticancer agents in patients with impaired liver function" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Cancer" "fecha" => "1998" "volumen" => "34" "paginaInicial" => "33" "paginaFinal" => "46" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 83 => array:3 [ "identificador" => "bib0420" "etiqueta" => "84." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Predicting etoposide toxicity: relationship to organ function and protein binding" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.1996.14.1.257" "Revista" => array:7 [ "tituloSerie" => "J Clin Oncol" "fecha" => "1996" "volumen" => "14" "paginaInicial" => "257" "paginaFinal" => "267" "link" => array:1 [ 0 => array:2 [ …2] ] "itemHostRev" => array:3 [ "pii" => "S0022534713061090" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 84 => array:3 [ "identificador" => "bib0425" "etiqueta" => "85." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Veno-occlusive disease of the liver after hemopoietic cell transplatnation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ …1] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur J Haematol" "fecha" => "2000" "volumen" => "64" "paginaInicial" => "281" "paginaFinal" => "291" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 85 => array:3 [ "identificador" => "bib0430" "etiqueta" => "86." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Etosposid (VP 16-213) induced hepatitis. 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Giuliano Ramadori*,*, Silke Cameron*

* Department of Gastroenterology and Endocrinology, Georg-August-University Göttingen

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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">A 62 years old patient with the first diagnosis of a cholangiocarcinoma in June 2006&#46; The MRCP &#40;A&#41; showed a strong intrahepatic cholestasis with high bilirubin levels &#40;E&#41;&#46; Therefore a PTC was performed&#46; The PTC &#40;B&#41; showed a dilation of the intrahepatic bile ducts and a subtotal stenosis of the DHC&#46; In a &#8220;Rendezvous-technique&#8221; &#40;PTC together with ERCP&#59; C&#41; it was possible to pass the DHC stenosis and place one stent in the right and one stent in the left main bile duct &#40;D&#41;&#46; The bilirubin levels decreased and a chemotherapy with gemcitabine was started&#46; Actually the patient has further on normal bilirubin levels &#40;E&#41;&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">The Liver is the Central Organ of Intermediate Metabolism and is Crucial in Host Defense</span><p id="p0005" class="elsevierStylePara elsevierViewall">The liver is the central organ of the intermediate metabolism and is the main source of plasma proteins &#40;e&#46; g&#46; albumin&#41;&#46; The parenchymal cells&#44; the hepatocytes&#44; comprise about 80&#37; of the liver mass and about 60&#37; of the total number of the adult liver cell population&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> They are responsible for the organization and for the performance of <span class="elsevierStyleItalic">intermediate metabolism&#44;</span> for the <span class="elsevierStyleItalic">metabolic detoxification</span> and for the <span class="elsevierStyleItalic">excretion of waste products</span>&#46; Whilst for most drugs&#44; hepatocyte function is drug-degradation&#44; for some it is the activation of prodrugs&#46; Therefore&#44; a normal functioning hepatocyte is a prerequisite for the administration of chemotherapy&#46; In case of abnormalities due to hepatocellular damage on the one hand&#44; or to a high demand for hepatocellular biosynthesis on the other hand&#44; this high-powered engine may get into trouble&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">For the correct execution and tight regulation of these processes&#44; the spatial relationship of the hepa-tocytes with the different cellular structures of the liver&#44; such as fenestrated sinusoidal endothelial cells&#44; Kupffer cells&#44; and bile canaliculi is important&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">Beneath the well known functions of the liver regarding intermediate metabolism and detoxification&#44; there is another equally relevant function&#44; the <span class="elsevierStyleItalic">clea-rance function</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> About 80&#37; of the body&#8217;s fixed tissue macrophages &#40;von Kupffer cells&#41; reside within the liver&#46; The von Kupffer cells are in direct contact with the portal blood&#44; streaming back from the gut or from the systemic circulation&#46; This blood may be heavily loaded with toxic &#40;lipopolysaccharide&#41; or infectious agents &#40;bacteria&#44; viruses&#41;&#44; cellular debris &#40;e&#46; g&#46; from erythrocytes&#41;&#44; undigested biomaterial or any other compounds that are not supposed to enter the systemic blood circulation&#46; Scavenging of all this material is achieved in the liver by von Kupffer cell-and sinusoidal endothelial cell-endocytosis&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Moreover&#44; humoral factors that are part of the innate immune system may ease hepatic clearance and maintain <span class="elsevierStyleItalic">host-defense mechanisms&#46;</span> Changes in the function of the liver immune cells have been reported after cytotoxic chemotherapy&#46;</p><p id="p0020" class="elsevierStylePara elsevierViewall">Alongside functional issues&#44; obstruction of the bile duct system prior to chemotherapy presents a problem in cancer patients which has to be solved before chemotherapy is started &#40;<a class="elsevierStyleCrossRef" href="#f0005">Figure I</a>&#41;&#46; Disturbance of the bile flow leads in fact to reduction of the hepatocellular function and to reduced protein synthesis&#46; The gastroenterologist is therefore the specialist again&#44; who should be contacted in such cases&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Basic Principles of Cytotoxic Chemotherapy</span><p id="p0025" class="elsevierStylePara elsevierViewall">Chemotherapy as the main nonsurgical remedy of cancer treatment is generally based on the cytotoxic effect of natural or synthetic agents taking advantage of a higher vulnerability of cancer cells as compared to normal cells&#46; However&#44; normal cells may be affected by cytotoxic chemotherapy as well&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Suscep-tibility to chemotherapy is linked to the proliferative rate of a cell population as seen in bone marrow cells or mucosal cells with high replication rates&#46; Inhibition of DNA replication and transcription via interference of cancer drugs either with the DNA strand&#44; with enzymes involved in DNA metabolism or DNA substrates may rank as the most important principle of cancer treatment directly inhibiting cell proliferation&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The Liver May Become A &#8220;Target&#8221; of and May Suffer From Cytotoxic Chemotherapy</span><p id="p0030" class="elsevierStylePara elsevierViewall">Replication of hepatocytes is low in normal liver&#44; but may reach a high level during liver regeneration after massive hepatocellular death or partial hepa-tectomy&#46;</p><p id="p0035" class="elsevierStylePara elsevierViewall">In the healthy liver&#44; with its low replication rate&#44; inhibition of hepatocellular replication during chemotherapy thus is not of primary matter&#46; Nevertheless&#44; systemic application of chemotherapeutics affecting DNA&#44; RNA or protein synthesis&#44; may affect hepatocellular function in several ways&#58;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Nausea and vomiting cause a reduction of nutrition&#59; reduced uptake of nutrients has been shown to induce a shrinkage of the liver that may reach a reduction in liver cell mass of almost 50&#37; under total starving&#46; Normal food uptake after fasting has been shown to induce DNA synthesis in hepatocytes with cellular replication &#40;DNA endoreplication&#41; resulting in polyploidy and presence of several nuclei in the hepatocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However&#44; even without a period of fas-ting&#44; highly metabolically active hepatocytes need normal DNA and RNA synthesis for normal protein synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Impact of Cytotoxic Chemotherapy on Liver Function&#58; Hepatocellular Dysfunction and Clinical Implications</span><p id="p0045" class="elsevierStylePara elsevierViewall">Most drugs tend to be lipophilic compounds that are taken up readily by the liver but that cannot be excreted easily unchanged in bile or urine&#46; Metabolic pathways are inducible and include a series of steps that alter the parent molecule&#44; synthesize conjugates of the drug or its metabolite with a more water-soluble moiety and comprise energy-dependent pathways to excrete either the parent molecule or its conjugates into the bile&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0050" class="elsevierStylePara elsevierViewall">Under chemotherapy&#44; up to 85&#37; of patients develop liver steatosis indicating disturbed lipid metabolism via altered lipoprotein synthesis in the hepato-cytes&#46; An increase of the hepatocellular lipid content &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>&#41; is responsible for higher vulnerability&#46; The higher vulnerability may&#44; in particular during repeated chemotherapy&#44; induce irreversible hepato-cellular damage through recruitment of inflammatory cells&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0055" class="elsevierStylePara elsevierViewall">Elevation of serum aminotransferases represents a frequent event during or after cytotoxic chemotherapy&#46; The hepatocellular sensibility to cytotoxic chemo-therapy depends on the particular chemotherapeutic agent&#44; giving rise to a classification of agents with high or low potential hepatotoxicity &#40;<a class="elsevierStyleCrossRef" href="#t0005">Table I</a>&#41;&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Impairment of Liver Function During Cytotoxic Chemotherapy&#58; Impact on Clearance Function</span><p id="p0060" class="elsevierStylePara elsevierViewall">As described above&#44; the liver is home of 80&#37; of all fixed tissue macrophages of the body&#46; It has to be assumed that this accumulation of mononuclear phagocytes in the liver reflects a high demand for clearance in this particular organ primarily conducted by Kupffer cells&#46; The turnover of Kupffer cells has been debated for decades&#44; and there is no final argument to what extent Kupffer cells are self-repli-cative or replaced by immigrating blood monocytes&#46; The mitotic index of Kupffer cells is quite low&#44; and increasing evidence has accumulated that Kupffer cells primarily derive from bone marrow cells&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Accordingly&#44; a numerous population of transient mo-nocytes has been reported in normal liver&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> On the other hand&#44; a large influx of blood monocytes is observed in the diseased liver&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> After chemotherapy with suppression of bone marrow cell replication&#44; the supply of Kupffer cell precursor cells is disturbed&#46; At the same time&#44; epithelial cell replication in the gut is also suppressed&#46; The increased permeability of the gut gives rise to a highly increased hepatic onflow of toxic and infectious agents demanding a faster turnover of hepatic macrophages&#46; This divergency may result in an increased risk for infections&#46; It has further been shown that cytotoxic chemotherapy impairs the phagocytotic activity of Kupffer ce-lls&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Reduced synthesis of humoral factors for host defense may also be critical in development of infections after cytotoxic chemotherapy&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Drug-Induced Liver Disease</span><p id="p0065" class="elsevierStylePara elsevierViewall">Drug-induced liver disease can mimic all forms of acute and chronic hepatobiliary diseases&#46; Liver injury is designated <span class="elsevierStyleItalic">hepatocellular</span> when the alanine transaminase &#40;ALT&#41; level is greater than 2 times the upper limit of normal &#40;ULN&#41; or the ALT&#47;alkaline phosphatase &#40;AP&#41; ratio is &#8805; 5&#59; <span class="elsevierStyleItalic">cholestatic</span> when the AP is greater than 2 times ULN or the ALT&#47;AP ratio is &#8804; 2&#59; and mixed when the ALT&#47;AP ratio is 2 to 5 and the individual values are greater than 2 times ULN&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">Hepatic dysfunction under chemotherapy mainly consists of abnormal biologic liver tests indicating chronic cholestasis with elevation in the levels of bilirubin&#44; alkaline phosphatase &#40;AP&#41;&#44; and gamma glutamyl transferase &#40;yGT&#41; with or without abnormal levels of aspartate aminotransferase &#40;AST&#41; and&#47;or alanine aminotransferase &#40;ALT&#41;&#46; The predominant clinical presentations resemble acute icteric hepatitis or cholestatic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">The development of hepatotoxicity is determined by the interplay of the <span class="elsevierStyleItalic">toxic potential of the drug</span> or its metabolites and the susceptibility of the patient as determined by <span class="elsevierStyleItalic">genetic</span> &#40;i&#46;e&#46; extensive or poor me-tabolizer&#41; and <span class="elsevierStyleItalic">environmental</span> factors&#46;</p><p id="p0080" class="elsevierStylePara elsevierViewall">Risk factors for drug-induced liver disease include&#58; age&#44; gender&#44; genetic or familial predisposition&#44; drug interactions &#40;concomitant drugs&#41;&#44; cross-reactivity of different drugs which have not been tolerated in the past&#44; alcohol &#40;abuse&#41;&#44; nutritional status and underlying liver or other diseases &#40;i&#46;e&#46; viral hepatitis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In cancer patients&#44; causes of abnormal liver tests are further toxicity of anticancer drugs&#44; toxicity of supportive medications&#44; radiation-induced liver disease&#44; tumor infiltration of the liver&#44; Budd-Chiari syndrome&#44; paraneoplatic syndrome&#44; graft-versus-host disease &#40;after stem cell transplantation&#41;&#44; fungal liver disease&#44; sepsis&#44; and hemolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Veno-Occlusive Disease of the Liver</span><p id="p0085" class="elsevierStylePara elsevierViewall">High-dose cytoreductive chemotherapy &#40;as given before bone-marrow transplantation&#41; which might be combined with radiotherapy&#44; carries the serious risk for the development of veno-occlusive disease &#40;VOD&#41; of the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The clinical hallmarks for the on-setting of this disease are jaundice&#44; painful hepatomegaly and fluid retention&#44; accompanied by high elevation of aminotransferases and later ascites and hepatic encephalopathy&#46; The basic pathophysiological mechanism of induction of VOD of the liver is supposed to be an injury of the endothelial cells of central veins and sublobular liver veins&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> A subsequent clotting activation results in occlusion of central veins&#44; sublobular veins and&#44; in the worst case&#44; of liver veins&#46; Fibri-nolysis may have a positive effect on the outcome of this disease&#44; and single cases of an emergency implantation of a transjugular portosystemic shunt &#40;TIPS&#41; have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> A final option for preventing the fatal outcome would be liver transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Differential Diagnosis of Elevated Liver Enzymes</span><p id="p0090" class="elsevierStylePara elsevierViewall">Differential diagnosis of elevated liver enzymes under chemotherapy has to include toxic effects from the tumor itself&#44; resulting i&#46;e&#46; from hepatic me-tastases&#44; tumor-induced portal vein thrombosis&#44; pa-raneoplastic syndromes&#44; infiltration with amyloid or light chain deposits or pre-existing liver disease&#44; and furthermore effects from co-medication and infectio-ns&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Causality assessment is necessary to determine the probability that liver injury is drug-induced&#46; It includes the following steps&#58;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><ul class="elsevierStyleList" id="li0005"><li class="elsevierStyleListItem" id="list0005"><span class="elsevierStyleLabel">&#8226;</span><p id="p0100" class="elsevierStylePara elsevierViewall">Latency of liver-enzyme elevation following the administration of the drug&#46;</p></li><li class="elsevierStyleListItem" id="list0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0105" class="elsevierStylePara elsevierViewall">Rate of resolution after dechallenge&#46;</p></li><li class="elsevierStyleListItem" id="list0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0110" class="elsevierStylePara elsevierViewall">Risk factors for the development of liver disease &#40;age&#44; alcohol&#44; pregnancy&#41;&#46;</p></li><li class="elsevierStyleListItem" id="list0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0115" class="elsevierStylePara elsevierViewall">Exclusion of other causes &#40;viral hepatitis&#44; ischemia&#44; biliary tract disease&#44; alcohol&#41;&#46;</p></li><li class="elsevierStyleListItem" id="list0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0120" class="elsevierStylePara elsevierViewall">Concomitant drugs&#46;</p></li><li class="elsevierStyleListItem" id="list0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0125" class="elsevierStylePara elsevierViewall">Track record of the patient&#8217;s charts&#47;of similar cases&#46;</p></li><li class="elsevierStyleListItem" id="list0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0130" class="elsevierStylePara elsevierViewall">Rechallenge with the drug &#40;in certain cases&#41;&#46;</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Genetic Predisposition and Drug-Metabolizing Enzymes</span><p id="p0135" class="elsevierStylePara elsevierViewall">The degradation and detoxification of many che-motherapeutics in the liver depends on the activity of a particular enzyme pathway that may be altered by hepatocellular dysfunction induced by the drug itself&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Moreover&#44; genetic variations or inhibition of degrading enzymes by non-cytotoxic drugs may delay hepatic metabolization of the cytotoxic agent&#44; thus increasing its toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> A contrary effect may be observed if the cytotoxic agent is in need of activation by a hepatic enzyme &#40;pro-drugs&#41;&#44; or if a drug-interaction increases the expression of a hepatic enzyme &#40;<a class="elsevierStyleCrossRef" href="#t0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Impaired detoxification may be accompanied by disturbed biliary excretion of hepa-tocytes due to a chemotherapy-included slow-down of a the hepatocellular metabolism-inducing ele-vation of serum parameters of cholestasis&#46;</p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0140" class="elsevierStylePara elsevierViewall">Furthermore&#44; enzyme polymorphisms of drug-metabolizing enzymes have to be taken into account&#44; such as thiopurine S-methyltransferases &#40;TMPT&#41;&#44; di-hydropyrimidine dehydrogenase &#40;DPD&#41;&#44; aldehyde de-hydrogenases &#40;ALDH&#41;&#44; glutathione S-transferases &#40;GST&#41;&#44; uridine diphosphate glucuronosyltransferases &#40;UGTs&#41; and cytochrome P450 &#40;CYP 450&#41; enzymes&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="p0145" class="elsevierStylePara elsevierViewall">It has been shown&#44; that genetic variants in the UDP-glucuronosyltransferase 1A1 predict the severe risk of neutropenia with irinotecan treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Lack of DPD results in severe 5-fluorouracil induced toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="p0150" class="elsevierStylePara elsevierViewall">For completion&#44; some tumors are able to overex-press multidrug-resistance genes&#44; resulting in poor responses of the tumor to chemotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="p0155" class="elsevierStylePara elsevierViewall">As a result evaluation of enzyme-polymorphisms as well as of drug-plasma levels is currently gaining increased importance for the improvement of indivi-dualized therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Liver Disease With Therapy Regimen Used for Gastrointestinal Tumors</span><p id="p0160" class="elsevierStylePara elsevierViewall">In case of chemotherapy-induced hepatotoxicity&#44; dose adjustment or change of the drug-combination may become necessary &#40;<a class="elsevierStyleCrossRef" href="#t0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><elsevierMultimedia ident="t0015"></elsevierMultimedia><p id="p0165" class="elsevierStylePara elsevierViewall">Drugs can be devided into <span class="elsevierStyleItalic">dose-dependent</span> or predictable hepatotoxins&#44; and <span class="elsevierStyleItalic">dose-independent</span> or unpredictable hepatotoxins&#46; Dose-dependent hepato-toxins generally require metabolic activation to a toxic metabolite and interfere with subcellular orga-nelles and biochemical processes at key sites such as mitochondria or canalicular bile secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Liver injury produced by dose-dependent hepatotoxins usually occurs after a short latent period &#40;hours&#41;&#44; and is characterized by zonal necrosis or microvesi-cular steatosis &#40;i&#46;e&#46; aflatoxins&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="p0170" class="elsevierStylePara elsevierViewall">Most clinically overt adverse hepatic events associated with drugs are unpredictable&#46; These events can be divided into apparent hypersensitivi-ty reactions associated with fever&#44; rash&#44; eosino-philia&#44; and a rapid response upon rechallenge&#44; versus presumed metabolic unpredictable &#40;idiosyncratic&#41; reactions&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">5-Fluorouracil &#40;5-FU&#41;</span><p id="p0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">5-FU</span> is the base of most combination therapies of gastrointestinal tumors&#46; It is an uracil analogue and antimetabolite that is metabolized mainly in the liver by dihydropyrimidindehydrogenase &#40;DPD&#41;&#46; In case of DPD-deficiency myelotoxicity and diarrhea are the most common toxic effects&#44; followed by mu-cositis&#44; hand-foot-syndrome and neurotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> 5-FU has been associated with hepatic steatosis on histological and radiological findings&#44; but has not been shown to affect morbidity or mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> 5-FU is fairly safe to use in patients with liver dysfunction&#44; although regular monitoring of liver tests is advised&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">C&#945;pecit&#945;bine</span> is an oral prodrug that is converted to fluorouracil in three enzymatic steps via carboxylesterase to 5&#8217;-Desoxy-5-Fluorocytidin &#40;5&#8217;-DFCR&#41;&#44; cytidin-deaminase to 5&#8217;-Desoxy-5-Fluorouri-din &#40;5&#8217;-DFUR&#41; and by thymidine phosphorylase &#40;TP&#41; to the active component 5-FU&#46; TP is an enzyme which is present at higher levels in some tumors and the liver than in other healthy tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Hyperbilirubi-naemia is common and usually reversible&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> It might be related to haemolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Oxaliplatin</span><p id="p0185" class="elsevierStylePara elsevierViewall">Oxaliplatin is a platinum analogue which ist given in combination with 5-FU&#46; It belongs to the alkylating chemotherapy agents which&#44; like Cis-or Carboplatin&#44; result in the formation of crosslinks within and between DNA strands&#46; Oxaliplatin is mainly excreted through the kidneys and does not undergo cytochrome P450 metabolism within the liver&#46; Hence it is tolerated by patients with liver dys-function&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> Nevertheless&#44; studies of patients undergoing liver metastasectomy after neoadjuvant oxaliplatin-based treatment have shown histological evidence of liver damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> Neoadjuvant chemotherapy with 5-FU and oxaliplatin-based regimes has been associated with vascular changes in heal-thy liver parenchyma&#44; more than steatosis&#46; Frequency of oxaliplatin-associated sinusoidal obstruction or dilatation syndrome varies in reports from 20&#8211;80&#37;&#44;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> a condition which might increase morbidity but not mortality after liver metastec-tomy&#46; Current recommendations are to limit the number of preoperative cycles if possible&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Irinotecan</span><p id="p0190" class="elsevierStylePara elsevierViewall">Irinotecan &#40;CPT-II&#41; is the other main combination partner of 5-FU in advanced colorectal carcinoma therapy&#46; It is a camptothecin analogue&#44; and is a prodrug which requires bioactivation in the liver by carboxyesterase to form the active and lipophilic metabolite SN-38&#46; SN-38 acts as a topoisomerase I poison and is approximately 100&#8211;1000-fold more cytotoxic than the parent drug&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Topoisomerases are enzymes which are responsible for the maintenance of DNA-topology during the S-phase&#46; Irinote-can and its active metabolite SN-38 form a complex with topoisomerase I and inhibit DNA-replication&#46; A similar substance is topotecan&#46; Etoposid inhibits DNA-Topoisomerase II&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="p0195" class="elsevierStylePara elsevierViewall">Irinotecan is subject to extensive metabolic conversion by various enzyme systems&#44; including esterases to form SN-38&#44; UGT1A1 mediating glucuronidation of SN-38&#44; as well as CYP3A4&#44; which forms several pharmacologically inactive oxidation products&#46; Elimination routes of irinotecan also depend on the presence of drug-transporting proteins&#44; notably P-glycoprotein and canalicular multispecific organic anion transporter&#44; present on the bile cana-licular membrane&#46; The various processes mediating drug elimination&#44; either through metabolic breakdown or excretion&#44; likely impact substantially on inter-individual variability&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">Toxic levels of irinotecan can accumulate from standard doses if glucuronidation is reduced&#44; as occurs in Gilbert&#8217;s-Meulengracht syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Elevated bilirubin and AP levels are associated with decreased irinotecan clearance&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="p0205" class="elsevierStylePara elsevierViewall">Irinotecan is associated with hepatic steatosis and steatohepatitis in up to 50&#37; of liver-resection samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Steatohepatitis has been associated with increased morbidity&#44; and increased mortality in some series&#44; after liver resection&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="p0210" class="elsevierStylePara elsevierViewall">It is generally more common to use oxaliplatin-based regimens than those that are irinotecan-based for neoadjuvant treatment before liver resection&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Irinotecan can also cause mild elevations of serum transaminases and bilirubin in up to 25&#37; of pa-tients&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Gemcitabine</span><p id="p0215" class="elsevierStylePara elsevierViewall">Gemcitabine &#40;2&#8217;&#44;2&#8217;-Difluordesoxycytidin&#41; is a pyri-midine&#47;deoxycytidine analogue which acts as anti-metabolite&#46; It is a pro-drug that&#44; once transported into the cell&#44; undergoes intracellular phosphoryla-tion and activation by deoxycytidine kinase&#46; Both gemcitabine diphosphate and gemcitabine triphos-phate inhibit processes required for DNA synthesis&#46; Incorporation of gemcitabine triphosphate &#40;dFdC-TP&#41; into DNA is most likely the major mechanism by which gemcitabine causes cell death&#46; After incorporation of the gemcitabine nucleotide on the end of the elongating DNA strand&#44; one deoxynucleotide is added and DNA polymerases are unable to proceed&#44; a process called <span class="elsevierStyleItalic">masked termination&#46;</span><a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="p0220" class="elsevierStylePara elsevierViewall">Active gemcitabine triphosphate is degraded by cytidine deaminase in liver&#44; blood and kidney to form an inactive metabolite&#58; 2&#8217;&#44;2&#8217;-difluorodeoxyuri-dine &#40;dFdU&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> It is eliminated by the kidney&#46;</p><p id="p0225" class="elsevierStylePara elsevierViewall">Administration of gemcitabine is associated with a mild rise in transaminases in up to 60&#37; of patients&#44; and in serum bilirubin in a small proportion of patients&#46; These changes are usually transient&#44; but are very rarely associated with severe hepatotoxici-ty&#46; <a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Monitoring of liver tests in patients who are receiving gemcitabine is recommended&#44; the expected mild rise in transaminases is usually of no clinical consequence&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In case of slightly elevated transami-nases&#44; gemcitabine is generally well tolerated without increased toxicity&#46; However&#44; in patients with primarily elevated bilirubin&#44; significant deterioration in liver function under therapy has been described&#46; Patients with elevated creatinine levels had significant toxicity even at reduced doses&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Dacarbacine</span><p id="p0230" class="elsevierStylePara elsevierViewall">Dacarbazine is an alkylating agent and crosslinks DNA during all phases of the cell cycle&#44; resulting in disruption of DNA function&#44; cell cycle arrest&#44; and apoptosis&#46; It is used in the therapy of advanced neuroendocrine tumors&#44; malignant melanoma&#44; hodgkins lymphoma and sarcoma&#46; Common side-effects include nausea and vomiting and bone-marrow suppression&#46; There are case reports which indicate that next to elevation of liver enzymes&#44; there might be hepatic veno-oclusive disease associated with the administration of Dacarbazine&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Imatinib</span><p id="p0235" class="elsevierStylePara elsevierViewall">Imatinib is an oral small-molecule tyrosine kina-se inhibitor&#44; effective to inhibit the BCR-ABL kinase in chronic myeloid leukaemia and the KIT tyrosine kinase and platelet-derived growth factor receptor in gastrointestinal stromal tumors &#40;GISTs&#41;&#46; Cases of severe liver injury are rare&#46; In the two large multicentre studies with 147 and 946 patients treated for GIST&#44; abnormal liver function tests were observed in 5&#46;4&#37; of treated patients &#40;including grade 3&#8211;4 toxicity in 2&#46;7&#37;&#41;&#44; and fatal liver disease occurred in 3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> In chronic myeloic leukemia imatinib was found to cause grade 2 or higher elevations in serum aminotransferases in 8&#37; of the treated patients and grade 3&#8211;4 elevations in 1&#8211;5&#37;&#46; Grade 3&#8211;4 elevations in serum bilirubin levels were reported in 0&#46;4&#8211;3&#46;5&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Sorafenib</span><p id="p0240" class="elsevierStylePara elsevierViewall">Sorafenib is an orally available multi-kinase inhibitor&#44; which has shown effectivity against hepatoce-llular carcinoma and renal-cell carcinoma&#46; It is mainly metabolized in the liver through both&#44; an oxidative pathway mediated by cytochrome P450 and UGT 1A9-mediated glucuronidation&#59; excretion is mostly faecally&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> A phase I study of sorafenib in patients with liver dysfunction who were devided into groups on the basis of bilirubin levels&#44; albumin levels&#44; and renal function&#44; showed that although drug clearance did not differ between groups&#44; dose-limiting toxic effects occurred with increasing biliru-bin levels and decreased albumin&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Cetuximab and panitumumab</span><p id="p0245" class="elsevierStylePara elsevierViewall">The epidermal growth factor receptor &#40;EGFR&#41; is a member of the ErbB family of closely related tyrosine kinase receptors&#58; EGFR &#40;ErbB-l&#47;HER-1&#41;&#44; ErbB-2 &#40;HER-2&#47;neu&#41;&#44; ErbB-3 &#40;HER-3&#41;&#44; and ErbB-4 &#40;HER-4&#41;&#46; Cetuximab and panitumumab are monoclonal antibodies that block the ligand binding site of the EGFR&#44; thus inhibiting intracellular signaling&#46; Cetuximab is a chimeric human-mouse antibody&#44; while panitumu-mab is a fully humanized monoclonal anti-EGFR an-tibody&#46; Common side effects of these antibodies include acneiform rash&#44; diarrhea&#44; and hypomagnesemia and hypersensitivity reactions that can be particularly severe with the chimeric antibody&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> Recent retrospective analyses from several large trials show that patients with tumors bearing the KRAS mutation do not respond to either cetuximab-or panitumumab-ba-sed therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69</span></a><span class="elsevierStyleSup">&#8211;</span><a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> These antibodies are generally used in combination with 5-FU based therapy&#46; However there are positive results for monotherapy in advanced disease&#46; In a case of chronic cholestasis and hy-perbilirubinemia caused by advanced liver involvement which prohibits second-line treatment&#44; combined antibody treatment with cetuximab and be-vacizumab &#40;an antibody against vascular endothelial growth factor&#41; was given and well-tolerated&#46; Clinical performance status as well as laboratory parameters improved rapidly and combined chemotherapy could be administered&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Bevacizumab</span><p id="p0250" class="elsevierStylePara elsevierViewall">Bevacizumab is a humanized antibody targeting vascular endothelial growth factor A &#40;VEGF-A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> It has been approved in first-and second-line treat-ment of metastatic colorectal cancer in combination with 5-FU and in lung cancer in combination with carboplatin and paclitaxel&#46; It has also shown benefit in metastatic breast cancer when combined with pa-clitaxel&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> The relatively well-known side effects include hypertension&#44; gastrointestinal perforation&#44; arterial thromboembolic events and postoperative bleeding or wound-healing complications&#46; Treatment with this antibody is safe&#44; even with elevated liver values&#46; Bevacizumab has no impact on hepatic stea-tosis and fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> As for sinusoidal obstructions&#44; results are contradictory&#46; One report states that be-vacizumab protects against the sinusoidal obstruction syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> whilst there are case reports of hepatic injury including veno-occlusive disease<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> and singular lesions with necrotic liver parenchyma with inflammatory reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> The reported side-effects however resolved after cessation of the thera-py&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> Even though these reactions are rare and unusual&#44; one should be aware that bevacizumab might cause portal hypertension with elevation of transaminases and bilirubin&#46;</p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Risks of Neoadjuvant Chemotherapy</span><p id="p0255" class="elsevierStylePara elsevierViewall">The changes &#40;steatosis&#44; steatohepatitis&#44; sinusoidal injury&#41; described above may be responsible for complications after surgery when neoadjuvant chemotherapy is performed in patients with advanced cancer&#46; The preoperative chemotherapy however has several advantages&#58; 1&#41; it downsizes tumors&#44; 2&#41; it increases curative resection rates and 3&#41; it converts some patients from having unresectable to resectable disease&#46; This kind of therapy has been however associated with an increased risk of perioperative morbidity or 90 days mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> In general&#44; there is no increase in complications even in the presence of severe &#40;&#62; 30&#37;&#41; steatosis&#44; when steatohepatitis &#40;stea-tosis with inflammation&#41; is excluded&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a></p><p id="p0260" class="elsevierStylePara elsevierViewall">Hepatic steatosis&#44; a mild manifestation of non-alcoholic fatty liver disease &#40;NAFLD&#41;&#44; may occur after treatment with 5-FU&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Steatohepatitis is for instance associated with irinotecan therapy&#46; Hepatic sinusoidal obstruction can occur with oxaliplatin treatment and appears to increase in severity with prolonged treatment &#40;&#62; 6 cycles&#41;&#46; It does however not appear to be associated with an increased risk of perioperative death&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> Bevacizumab can be used safely when discontinued &#62; 5 weeks before liver re-section&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Future Aspects</span><p id="p0265" class="elsevierStylePara elsevierViewall">Cancer continues to be one of the major causes of mortality throughout the world&#46; Modern combination chemotherapy allows for a longer time-to-progression &#40;TTP&#41; and longer overall survival &#40;OS&#41; even in advanced disease - resulting in a prolonged treatment&#46; Longer treatment times lead to increased toxic effects&#44; especially in an aging patient collective&#46; Whilst the <span class="elsevierStyleItalic">maximal tolerable dose</span> &#40;MTD&#41; might be given at the beginning of a therapy and particularly in the neoadjuvant and adjuvant treatment settings&#44; it might not be possible to continue this treatment over a longer period&#44; especially in palliative treatment&#46;</p><p id="p0270" class="elsevierStylePara elsevierViewall">Therefore&#44; we should ask ourselves&#44; what would be the <span class="elsevierStyleItalic">minimal effective dose</span> &#40;MED&#41; to treat our long-term patients&#44; and when to change&#46; Whilst <span class="elsevierStyleItalic">prognostic biomarkers</span> help to give us information about the therapeutic outcome of a specific disease&#44; <span class="elsevierStyleItalic">predictive biomarkers</span> might help us to anticipate the effect of a specific therapy for this disease whilst keeping the side effects tolerable&#46;</p><p id="p0275" class="elsevierStylePara elsevierViewall">Accounting for further individual parameters of the patients such as age&#44; gender and disease stage&#44; matched to the expected side effects under a given dose&#44; the efficacy of a treatment as well as the quality of life of our tumor patients&#44; shall be maintained as good as possible&#46;</p></span></span>"
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          "identificador" => "xres1217525"
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            0 => array:1 [
              "identificador" => "abs0005"
            ]
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        1 => array:2 [
          "identificador" => "xpalclavsec1132906"
          "titulo" => "Key words"
        ]
        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "The Liver is the Central Organ of Intermediate Metabolism and is Crucial in Host Defense"
        ]
        3 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Basic Principles of Cytotoxic Chemotherapy"
        ]
        4 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "The Liver May Become A &#8220;Target&#8221; of and May Suffer From Cytotoxic Chemotherapy"
        ]
        5 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Impact of Cytotoxic Chemotherapy on Liver Function&#58; Hepatocellular Dysfunction and Clinical Implications"
        ]
        6 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Impairment of Liver Function During Cytotoxic Chemotherapy&#58; Impact on Clearance Function"
        ]
        7 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Drug-Induced Liver Disease"
        ]
        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Veno-Occlusive Disease of the Liver"
        ]
        9 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Differential Diagnosis of Elevated Liver Enzymes"
        ]
        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Genetic Predisposition and Drug-Metabolizing Enzymes"
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        11 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Liver Disease With Therapy Regimen Used for Gastrointestinal Tumors"
          "secciones" => array:9 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "5-Fluorouracil &#40;5-FU&#41;"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Oxaliplatin"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Irinotecan"
            ]
            3 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Gemcitabine"
            ]
            4 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Dacarbacine"
            ]
            5 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Imatinib"
            ]
            6 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Sorafenib"
            ]
            7 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Cetuximab and panitumumab"
            ]
            8 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Bevacizumab"
            ]
          ]
        ]
        12 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Risks of Neoadjuvant Chemotherapy"
        ]
        13 => array:2 [
          "identificador" => "sec0105"
          "titulo" => "Future Aspects"
        ]
        14 => array:1 [
          "titulo" => "Reference"
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    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Key words"
          "identificador" => "xpalclavsec1132906"
          "palabras" => array:4 [
            0 => "Chemotherapy"
            1 => "Liver"
            2 => "Side effects"
            3 => "Host defence"
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">The liver is the largest parenchymatous organ of the body and central for intermediate metabolism&#46; Its close contact to the portal blood streaming back from the gut and the systemic circulation is a prerequisite for the various processes ongoing on cellular level&#46; The spatial relationship of the hepatocytes with the different cellular structures of the liver&#44; such as fenestrated sinusoidal endothelial cells&#44; Kupffer cells&#44; and bile canaliculi is important for the organization and performance of the <span class="elsevierStyleItalic">intermediate metabolism</span> of nutrients &#40;proteins&#44; glucose and fatty acids&#41;&#44; for the <span class="elsevierStyleItalic">clearance</span> of toxic or infectious agents&#44; for <span class="elsevierStyleItalic">metabolic detoxification</span> and for the <span class="elsevierStyleItalic">excretion</span> of waste products&#46;</p><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">The administration of chemotherapy is a challenge for the tight regulation and balance of these processes&#46; As most drugs tend to be lipophilic&#44; they are readily taken up by the liver&#46; Under chemotherapy&#44; up to 85&#37; of patients develop liver steatosis&#46; Steatohepatitis is the more serious event&#44; especially if accompanied by an increase in bilirubin levels&#46;</p><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Modern understanding of the efficacy&#44; safety and tolerability of combination chemotherapy has to increasingly include the individual context of a patient&#44; such as age&#44; gender&#44; nutritional status&#44; underlying diseases&#44; genetic predisposition&#44; as well as the cross-reactivity of the different drugs&#46;</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">This review tries to capture the various effects of chemotherapy on the liver&#44; with a focus on chemothe-rapeutical compounds used for the treatment of gastrointestinal cancers&#46;</p></span>"
      ]
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      0 => array:7 [
        "identificador" => "f0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">A 62 years old patient with the first diagnosis of a cholangiocarcinoma in June 2006&#46; The MRCP &#40;A&#41; showed a strong intrahepatic cholestasis with high bilirubin levels &#40;E&#41;&#46; Therefore a PTC was performed&#46; The PTC &#40;B&#41; showed a dilation of the intrahepatic bile ducts and a subtotal stenosis of the DHC&#46; In a &#8220;Rendezvous-technique&#8221; &#40;PTC together with ERCP&#59; C&#41; it was possible to pass the DHC stenosis and place one stent in the right and one stent in the left main bile duct &#40;D&#41;&#46; The bilirubin levels decreased and a chemotherapy with gemcitabine was started&#46; Actually the patient has further on normal bilirubin levels &#40;E&#41;&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "f0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Liver-ste&#945;tosis induced by chemotherapy&#44; H&#38;E staining&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "t0005"
        "etiqueta" => "Table I"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="npara0005" class="elsevierStyleSimplePara elsevierViewall">&#43;&#43;&#43; very often&#46; &#43;&#43; often&#46; &#43; rare&#46; &#40;&#43;&#41; very rare&#46; 0 no hepato-toxicity</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t  " align="left" valign="middle" scope="col">Hepatotoxicity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="middle">Methotrexate&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="middle">&#43;&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Asparaginase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Carmustine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Mercatopurin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Capecitabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Chlorambucil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cyclophosphamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cytarabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dacarbazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Etoposide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Gemcitabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Mitomycin C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Streptozocin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Busulfan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<span class="elsevierStyleSup">&#43;</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cisplatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<span class="elsevierStyleSup">&#43;</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">5-FU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Irinotecan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Imatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Oxaliplatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Vincristine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;&#43;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Bevacizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cetuximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Epirubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Hydroxyurea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab2078569.png"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Hepatotoxicity of cytotoxic chemotherapeutics&#46;</p>"
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      3 => array:7 [
        "identificador" => "t0010"
        "etiqueta" => "Table 2"
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        "tabla" => array:2 [
          "leyenda" => "<p id="npara0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">d&#58;</span> downregulation&#46; <span class="elsevierStyleBold">u&#58;</span> upregulation of the enzyme by the agent</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "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"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Drug metabolizing enzymes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Interaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cytochrome P450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">CYP2B6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cyclophosphamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">CYP2C8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Paclitaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">CYP3A4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Etoposide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Ketoconazole &#40;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Vinca alkaloids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Erythromycin &#40;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Ifosfamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Grapefruit joice &#40;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Corticosteroids &#40;u&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Irinotecan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Phenytoin &#40;u&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Ketoreductase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Anthracyclines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Carboxylesterases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Irinotecan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dihydropyrimidine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">5-Fluorouracil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dehydrogenase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Liver chemotherapeutics-metabolizing enzymes and interaction with drugs&#46;</p>"
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      ]
      4 => array:7 [
        "identificador" => "t0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="npara0015" class="elsevierStyleSimplePara elsevierViewall">Table modified after&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "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"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Drug name&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Liver toxic effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Frequency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Severity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Dose modification&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Fluorouracil &#40;5-FU&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Steatosis Hepatoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Subclinical Usually Subclinical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">No dose adjustment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Oxaliplatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Vascular changes&#58; Sinusoidal obstruction or dilatation Syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common &#40;20&#8211;80&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Might increase morbidity&#44; but not mortality after liver Resection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">No dose adjustment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Increased bilirubin&#46; AST or AP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">No effect on drug clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Irinotecan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Steatosis and steatohepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common &#40;25&#8211;50&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Steatohepatitis can Increase morbidity If used before liver Resection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Increased AST alone no increase of toxic effects increase of Bilirubin&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Increased aminotransferases and bilirubin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Up to 25&#37; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Usually reversible&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Neutropenia and diarrhea&#44; dose reduction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Capecitabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Hyperbilirubinaemia&#44; usually without increased AP and &#947;GT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common &#40;23&#8211;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Grad 3&#8211;4 in up to 23&#37; of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">No dose adjustmen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Cisplatin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">increased aminotransferases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common &#40;with high doses&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Usually transient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Unlikely to need dose adjustment&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Steatosis and cholectasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Usually transient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">mainly renal excretion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dacarbazine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Case report of fulminate liver failure &#40;thrombotic occlusions&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Can be life threatening&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Doxorubicin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Idiosyncratic reactions&#44; including increased aminotransferases and bilirubin &#40;myelosuppression&#44; mucositis&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Usually transient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dose adjustment with elevated bilirubin levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Etoposide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">In pre-existing liver disease&#58; Mild to moderate impairment&#58; no pharmacokinetic effect&#44; Severe impairment&#58; myelosuppression&#44; mucositis&#46; Decreased albumin increases unbound drug concentration and increases haematological toxic effects Veno-occlusive disease in higher doses Case reports of severe hepatocellular damage at standard doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Common in bone-marrow transplant-tation &#40;10&#8211;25&#37;&#41; Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Severe and life-threatening Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Unclear &#40;increase renal crearance might compensate&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">84</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">86</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Gemcitabine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Increased aminotransferases Increased bilirubin Case reports of fatal cholestatic hepatotoxicity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Veri common &#40;up To 60&#37;&#41; Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Generally transient and reversible Deterioration of Liver function Can be fatal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">No dose adjustment Reduce dose &#40;20&#37;&#41; and increased if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Imatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Increased aminotransferases or bilirubin Liver necrosis of failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">5&#8211;8&#37; Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">2&#8211;8&#37; grade 3&#8211;4 Case reports of Fatalities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Stop treatment if hepatotoxicity develops&#44; should probably not Rechallenge&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">In pre-existing liver disease&#58; clearance does not differ between patient cohorts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">Dose adjustment with elevated bilirubin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="middle">&#40;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Chemotherapeutic agents and associated toxic liver effects&#46; Table modified after&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p>"
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      "titulo" => "Reference"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bs0005"
          "bibliografiaReferencia" => array:86 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Developmental anatomy and normal structure"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "MacSween R&#46;N&#46;M&#46;"
                            1 => "Desmet V&#46;J&#46;"
                            2 => "Roskams T&#46;"
                            3 => "Scothorne R&#46;J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:4 [
                        "editores" => "MacSweenR&#46;N&#46;M&#46;, BurtA&#46;D&#46;, PortmannB&#46;C&#46;"
                        "titulo" => "Pathology of the liver"
                        "paginaInicial" => "1"
                        "serieFecha" => "2002"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2&#46;"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Roy-Chowdhury N&#44; Roy-Chowdhury J&#46; Liver Physiology and Energy Metabolism&#46; In&#58; Feldman M&#44; Friedman LS&#44; Brandt LJ &#40;eds&#46;&#41;&#46; Gastrointestinal and Liver Disease&#46; 2nd&#46; Ed&#46; Philadelphia&#59; 2006&#44; p&#46; 1551&#46;"
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver endocytosis and Kupffer cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Toth C&#46;A&#46;"
                            1 => "Thomas P&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:8 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "1992"
                        "volumen" => "16"
                        "numero" => "1"
                        "paginaInicial" => "255"
                        "paginaFinal" => "266"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1319954"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283812007087"
                          "estado" => "S300"
                          "issn" => "03022838"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional spectrum of sinusoidal endothelial liver cells&#46; Filtration&#44; endocytosis&#44; synthetic capacities and intercellular communication"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Rieder H&#46;"
                            1 => "Meyer zum Buschenfelde K&#46;H&#46;"
                            2 => "Ramadori G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1992"
                        "volumen" => "15"
                        "numero" => "1-2"
                        "paginaInicial" => "237"
                        "paginaFinal" => "250"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1506642"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cytotoxic drugs&#44; programmed cell death&#44; and the immune system&#58; defining new roles in an old play"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Debatin K&#46;M&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/jnci/89.11.750"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Natl Cancer Inst"
                        "fecha" => "1997"
                        "volumen" => "89"
                        "numero" => "11"
                        "paginaInicial" => "750"
                        "paginaFinal" => "751"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9182966"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An alteration in the nuclei of rat liver cells in starvation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Parr L&#46;"
                            1 => "Mossberg S&#46;M&#46;"
                            2 => "Rosenzweig M&#46;W&#46;"
                            3 => "Breslar E&#46;I&#46;"
                            4 => "Clark G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:4 [
                        "edicion" => "116th&#46; Ed&#46;"
                        "fecha" => "2005"
                        "paginaInicial" => "457"
                        "paginaFinal" => "468"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Influence of malnutrition on regeneration and composition of the liver in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Skullman S&#46;"
                            1 => "Ihse I&#46;"
                            2 => "Larsson J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Acta Chir Scand"
                        "fecha" => "1990"
                        "volumen" => "156"
                        "numero" => "10"
                        "paginaInicial" => "717"
                        "paginaFinal" => "722"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2264430"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver Disease Caused by Drugs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Teoh N&#46;C&#46;"
                            1 => "Farrell G&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:5 [
                        "editores" => "FledmanM&#46;, FriedmanL&#46;S&#46;, BrandtL&#46;J&#46;"
                        "titulo" => "Gastrointestinal and Liver Disease"
                        "paginaInicial" => "1807"
                        "edicion" => "2nd&#46; Ed&#46;"
                        "serieFecha" => "2006"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cell biology and kinetics of Kupffer cells in the liver"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Wake K&#46;"
                            1 => "Decker K&#46;"
                            2 => "Kirn A&#46;"
                            3 => "Knook D&#46;L&#46;"
                            4 => "McCuskey R&#46;S&#46;"
                            5 => "Bouwens L&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Int Rev Cytol"
                        "fecha" => "1989"
                        "volumen" => "118"
                        "paginaInicial" => "173"
                        "paginaFinal" => "229"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2691426"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0090429510017760"
                          "estado" => "S300"
                          "issn" => "00904295"
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                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional characterization of two different Kupffer cell populations of normal rat liver"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Armbrust T&#46;"
                            1 => "Ramadori G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1996"
                        "volumen" => "25"
                        "numero" => "4"
                        "paginaInicial" => "518"
                        "paginaFinal" => "528"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8912152"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mononuclear phagocytes of acutely injured rat liver abundantly synthesize and secrete fibronectin in contrast to Kupffer cells of normal liver"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Armbrust T&#46;"
                            1 => "Ramadori G&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/bbrc.1995.2194"
                      "Revista" => array:8 [
                        "tituloSerie" => "Biochem Biophys Res Commun"
                        "fecha" => "1995"
                        "volumen" => "213"
                        "numero" => "3"
                        "paginaInicial" => "752"
                        "paginaFinal" => "758"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7654234"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022534714001979"
                          "estado" => "S300"
                          "issn" => "00225347"
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                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Alteration of rat Kupffer cell function following mitomycin-C administration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Bodenheimer H&#46; Jr&#46;"
                            1 => "Charland C&#46;"
                            2 => "Leith J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jlb.43.3.265"
                      "Revista" => array:8 [
                        "tituloSerie" => "J Leukoc Biol"
                        "fecha" => "1988"
                        "volumen" => "43"
                        "numero" => "3"
                        "paginaInicial" => "265"
                        "paginaFinal" => "270"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3125296"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283816302007"
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                          "issn" => "03022838"
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                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Causality assessment versus guilt-by-association in drug hepatotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Kaplowitz N&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2001.21083"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2001"
                        "volumen" => "33"
                        "numero" => "1"
                        "paginaInicial" => "308"
                        "paginaFinal" => "310"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11124850"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of two clinical scales for causality assessment in hepatotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Lucena M&#46;I&#46;"
                            1 => "Camargo R&#46;"
                            2 => "Andrade R&#46;J&#46;"
                            3 => "Perez-Sanchez C&#46;J&#46;"
                            4 => "Sanchez D&#46;L&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/jhep.2001.20645"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hepatology"
                        "fecha" => "2001"
                        "volumen" => "33"
                        "numero" => "1"
                        "paginaInicial" => "123"
                        "paginaFinal" => "130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11124828"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug induced liver disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Kaplowitz N&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:4 [
                        "fecha" => "2007"
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                        "editorial" => "Informa Health Care"
                        "editorialLocalizacion" => "NY"
                      ]
                    ]
                  ]
                ]
              ]
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            15 => array:3 [
              "identificador" => "bib0080"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer Chemotherapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "DeLeve L&#46;D&#46;"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "KaplowitzN&#46;, DeLeveL&#46;D&#46;"
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                        "paginaFinal" => "662"
                        "edicion" => "2nd&#46; Ed&#46;"
                        "serieFecha" => "2007"
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                    ]
                  ]
                ]
              ]
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            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Veno-occlusive disease of the liver"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Bearman S&#46;I&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Curr Opin Oncol"
                        "fecha" => "2000"
                        "volumen" => "12"
                        "numero" => "2"
                        "paginaInicial" => "103"
                        "paginaFinal" => "109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10750719"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Toxic injury to hepatic sinusoids&#58; sinusoidal obstruction syndrome &#40;venoocclusive disease&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            1 => "Shulman H&#46;M&#46;"
                            2 => "McDonald G&#46;B&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1055/s-2002-23204"
                      "Revista" => array:7 [
                        "tituloSerie" => "Semin Liver Dis"
                        "fecha" => "2002"
                        "volumen" => "22"
                        "numero" => "1"
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                        "paginaFinal" => "42"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11928077"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful treatment of hepatic veno-occlusive disease in a peripheral blood progenitor cell transplant patient with a transjugular intrahepatic portosystemic stent-shunt &#40;TIPS&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "de la Rubia J&#46;"
                            1 => "Carral A&#46;"
                            2 => "Montes H&#46;"
                            3 => "Urquijo J&#46;J&#46;"
                            4 => "Sanz G&#46;F&#46;"
                            5 => "Sanz M&#46;A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Haematologica"
                        "fecha" => "1996"
                        "volumen" => "81"
                        "numero" => "6"
                        "paginaInicial" => "536"
                        "paginaFinal" => "539"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9009442"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Orthotopic liver transplantation for venoocclusive disease complicating autologous bone marrow transplantation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Norris S&#46;"
                            1 => "Crosbie O&#46;"
                            2 => "McEntee G&#46;"
                            3 => "Traynor O&#46;"
                            4 => "Nolan N&#46;"
                            5 => "McCann S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Transplantation"
                        "fecha" => "1997"
                        "volumen" => "63"
                        "numero" => "10"
                        "paginaInicial" => "1521"
                        "paginaFinal" => "1524"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9175821"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatotoxicity of chemotherapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "Floyd J&#46;"
                            1 => "Mirza I&#46;"
                            2 => "Sachs B&#46;"
                            3 => "Perry M&#46;C&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.seminoncol.2005.11.002"
                      "Revista" => array:7 [
                        "tituloSerie" => "Semin Oncol"
                        "fecha" => "2006"
                        "volumen" => "33"
                        "numero" => "1"
                        "paginaInicial" => "50"
                        "paginaFinal" => "67"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16473644"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human drug metabolism in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Sitar D&#46;S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Pharmacol Ther"
                        "fecha" => "1989"
                        "volumen" => "43"
                        "numero" => "3"
                        "paginaInicial" => "363"
                        "paginaFinal" => "375"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2682685"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug metabolism polymorphisms as modulators of cancer susceptibility"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Taningher M&#46;"
                            1 => "Malacarne D&#46;"
                            2 => "Izzotti A&#46;"
                            3 => "Ugolini D&#46;"
                            4 => "Parodi S&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s1383-5742(99)00005-8"
                      "Revista" => array:7 [
                        "tituloSerie" => "Mutat Res"
                        "fecha" => "1999"
                        "volumen" => "436"
                        "numero" => "3"
                        "paginaInicial" => "227"
                        "paginaFinal" => "261"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10354524"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The role of pro-drug therapy in the treatment of cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Ferguson M&#46;J&#46;"
                            1 => "Ahmed F&#46;Y&#46;"
                            2 => "Cassidy J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1054/drup.2001.0207"
                      "Revista" => array:8 [
                        "tituloSerie" => "Drug Resist Updat"
                        "fecha" => "2001"
                        "volumen" => "4"
                        "numero" => "4"
                        "paginaInicial" => "225"
                        "paginaFinal" => "232"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11991677"
                            "web" => "Medline"
                          ]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022534713051392"
                          "estado" => "S300"
                          "issn" => "00225347"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacogenetics and cancer chemotherapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Iyer L&#46;"
                            1 => "Ratain M&#46;J&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "1998"
                        "volumen" => "34"
                        "numero" => "10"
                        "paginaInicial" => "1493"
                        "paginaFinal" => "1499"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9893619"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Ando Y&#46;"
                            1 => "Ueoka H&#46;"
                            2 => "Sugiyama T&#46;"
                            3 => "Ichiki M&#46;"
                            4 => "Shimokata K&#46;"
                            5 => "Hasegawa Y&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Ther Drug Monit"
                        "fecha" => "2002"
                        "volumen" => "24"
                        "numero" => "1"
                        "paginaInicial" => "111"
                        "paginaFinal" => "116"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11805731"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Irinotecan pharmacogenetics&#58; influence of pharmacodynamic genes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Hoskins J&#46;M&#46;"
                            1 => "Marcuello E&#46;"
                            2 => "Altes A&#46;"
                            3 => "Marsh S&#46;"
                            4 => "Maxwell T&#46;"
                             …1
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/1078-0432.CCR-07-1472"
                      "Revista" => array:8 [
                        "tituloSerie" => "Clin Cancer Res"
                        "fecha" => "2008"
                        "volumen" => "14"
                        "numero" => "6"
                        "paginaInicial" => "1788"
                        "paginaFinal" => "1796"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022346817305407"
                          "estado" => "S300"
                          "issn" => "00223468"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2004.07.173"
                      "Revista" => array:8 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2004"
                        "volumen" => "22"
                        "numero" => "8"
                        "paginaInicial" => "1382"
                        "paginaFinal" => "1388"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S1078143913001129"
                          "estado" => "S300"
                          "issn" => "10781439"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dihydropyrimidine dehydrogenase&#58; its role in 5-fluorouracil clinical toxicity and tumor resistance"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Cancer Res"
                        "fecha" => "1999"
                        "volumen" => "5"
                        "numero" => "10"
                        "paginaInicial" => "2672"
                        "paginaFinal" => "2673"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MDR1 &#40;multidrug resistance&#41; gene expression in human primary liver cancer and cirrhosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "J Hepatol"
                        "fecha" => "1993"
                        "volumen" => "18"
                        "numero" => "2"
                        "paginaInicial" => "168"
                        "paginaFinal" => "172"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage&#58; results of a multicenter randomized trial of patients with metastatic colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2007.13.3934"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2008"
                        "volumen" => "26"
                        "numero" => "13"
                        "paginaInicial" => "2099"
                        "paginaFinal" => "2105"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32&#46;"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Yoo C&#46; A cross-sectional study of imatinib serum levels in patients with advanced GIST&#46; Abstract 161 ed&#46; 2010&#46;"
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemotherapy dosing in the setting of liver dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncology &#40;Williston Park&#41;"
                        "fecha" => "2005"
                        "volumen" => "19"
                        "numero" => "8"
                        "paginaInicial" => "1057"
                        "paginaFinal" => "1063"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Part II&#58; Liver function in oncology&#58; towards safer chemotherapy use"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(08)70307-3"
                      "Revista" => array:8 [
                        "tituloSerie" => "Lancet Oncol"
                        "fecha" => "2008"
                        "volumen" => "9"
                        "numero" => "12"
                        "paginaInicial" => "1181"
                        "paginaFinal" => "1190"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283814001651"
                          "estado" => "S300"
                          "issn" => "03022838"
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Part I&#58; Liver function in oncology&#58; biochemistry and beyond"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(08)70279-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet Oncol"
                        "fecha" => "2008"
                        "volumen" => "9"
                        "numero" => "11"
                        "paginaInicial" => "1092"
                        "paginaFinal" => "1101"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Molecular pathogenesis of cholestasis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM199810223391707"
                      "Revista" => array:8 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "1998"
                        "volumen" => "339"
                        "numero" => "17"
                        "paginaInicial" => "1217"
                        "paginaFinal" => "1227"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022534709005412"
                          "estado" => "S300"
                          "issn" => "00225347"
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                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Histopathology of drug-induced liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "KaplowitzN&#46;, DeLeveL&#46;D&#46;"
                        "titulo" => "Drug-induced liver disease"
                        "paginaInicial" => "237"
                        "paginaFinal" => "289"
                        "edicion" => "2nd edition ed&#46;"
                        "serieFecha" => "2007"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The contribution of deleterious DPYD gene sequence variants to fluoropyrimidine toxicity in British cancer patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00280-009-1147-x"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Chemother Pharmacol"
                        "fecha" => "2010"
                        "volumen" => "65"
                        "numero" => "2"
                        "paginaInicial" => "403"
                        "paginaFinal" => "406"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.1993.11.12.2386"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1993"
                        "volumen" => "11"
                        "numero" => "12"
                        "paginaInicial" => "2386"
                        "paginaFinal" => "2390"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
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              ]
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            39 => array:3 [
              "identificador" => "bib0200"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Demonstration of hepatic steatosis by computerized tomography in patients receiving 5-fluorouracil-based therapy for advanced colorectal cancer"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
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                    0 => array:2 [
                      "doi" => "10.1038/bjc.1998.333"
                      "Revista" => array:7 [
                        "tituloSerie" => "Br J Cancer"
                        "fecha" => "1998"
                        "volumen" => "77"
                        "numero" => "11"
                        "paginaInicial" => "2008"
                        "paginaFinal" => "2011"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                      ]
                    ]
                  ]
                ]
              ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/bjs.5719"
                      "Revista" => array:8 [
                        "tituloSerie" => "Br J Surg"
                        "fecha" => "2007"
                        "volumen" => "94"
                        "numero" => "3"
                        "paginaInicial" => "274"
                        "paginaFinal" => "286"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283808008609"
                          "estado" => "S300"
                          "issn" => "03022838"
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                  ]
                ]
              ]
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            41 => array:3 [
              "identificador" => "bib0210"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdg302"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2003"
                        "volumen" => "14"
                        "numero" => "7"
                        "paginaInicial" => "1142"
                        "paginaFinal" => "1147"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            42 => array:3 [
              "identificador" => "bib0215"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s002800050043"
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                        "tituloSerie" => "Cancer Chemother Pharmacol"
                        "fecha" => "2000"
                        "volumen" => "45"
                        "numero" => "4"
                        "paginaInicial" => "291"
                        "paginaFinal" => "297"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral capecitabine as an alternative to i&#46;v&#46; 5-fluorouracil-based adjuvant therapy for colon cancer&#58; safety results of a randomized&#44; phase III trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdg500"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2003"
                        "volumen" => "14"
                        "numero" => "12"
                        "paginaInicial" => "1735"
                        "paginaFinal" => "1743"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            44 => array:3 [
              "identificador" => "bib0225"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer&#58; results of a large phase III study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2001.19.21.4097"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2001"
                        "volumen" => "19"
                        "numero" => "21"
                        "paginaInicial" => "4097"
                        "paginaFinal" => "4106"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fluoropyrimidine therapy&#58; hyperbilirubinemia as a consequence of hemolysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00280-005-1011-6"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Chemother Pharmacol"
                        "fecha" => "2005"
                        "volumen" => "56"
                        "numero" => "6"
                        "paginaInicial" => "594"
                        "paginaFinal" => "602"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction&#58; a preliminary report of the National Cancer Institute Organ Dysfunction Working Group"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Semin Oncol"
                        "fecha" => "2003"
                        "volumen" => "30"
                        "numero" => "4 Suppl&#46; 15"
                        "paginaInicial" => "14"
                        "paginaFinal" => "19"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            47 => array:3 [
              "identificador" => "bib0240"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2006.05.8156"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2006"
                        "volumen" => "24"
                        "numero" => "31"
                        "paginaInicial" => "4983"
                        "paginaFinal" => "4990"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            48 => array:3 [
              "identificador" => "bib0245"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejso.2007.07.007"
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur J Surg Oncol"
                        "fecha" => "2008"
                        "volumen" => "34"
                        "numero" => "6"
                        "paginaInicial" => "609"
                        "paginaFinal" => "614"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            49 => array:3 [
              "identificador" => "bib0250"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdh095"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2004"
                        "volumen" => "15"
                        "numero" => "3"
                        "paginaInicial" => "460"
                        "paginaFinal" => "466"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            50 => array:3 [
              "identificador" => "bib0255"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2005.05.3074"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2006"
                        "volumen" => "24"
                        "numero" => "13"
                        "paginaInicial" => "2065"
                        "paginaFinal" => "2072"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              ]
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            51 => array:3 [
              "identificador" => "bib0260"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Lessons learned from the irinotecan metabolic pathway"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Curr Med Chem"
                        "fecha" => "2003"
                        "volumen" => "10"
                        "numero" => "1"
                        "paginaInicial" => "41"
                        "paginaFinal" => "49"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            52 => array:3 [
              "identificador" => "bib0265"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Etoposide&#58; Discovery and medicinal chemistry&#46; Current medicinal chemistry"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Libro" => array:6 [
                        "edicion" => "11th&#46; Ed&#46;"
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                        "paginaFinal" => "66"
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              ]
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            53 => array:3 [
              "identificador" => "bib0270"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical pharmacokinetics and metabolism of irinotecan &#40;CPT-11&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Clin Cancer Res"
                        "fecha" => "2001"
                        "volumen" => "7"
                        "numero" => "8"
                        "paginaInicial" => "2182"
                        "paginaFinal" => "2194"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            54 => array:3 [
              "identificador" => "bib0275"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2002.03.123"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2002"
                        "volumen" => "20"
                        "numero" => "21"
                        "paginaInicial" => "4303"
                        "paginaFinal" => "4312"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              "identificador" => "bib0280"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jamcollsurg.2005.01.024"
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                        "tituloSerie" => "J Am Coll Surg"
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                        "volumen" => "200"
                        "numero" => "6"
                        "paginaInicial" => "845"
                        "paginaFinal" => "853"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Topoisomerase I inhibitors&#46; An overview of the camptothecin analogs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
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                        "tituloSerie" => "Hematol Oncol Clin North Am"
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                        "volumen" => "8"
                        "numero" => "2"
                        "paginaInicial" => "333"
                        "paginaFinal" => "355"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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            57 => array:3 [
              "identificador" => "bib0290"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gemcitabine&#58; metabolism&#44; mechanisms of action&#44; and self-potentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Semin Oncol"
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                        "volumen" => "22"
                        "numero" => "4 Suppl&#46; 11"
                        "paginaInicial" => "3"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                      ]
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                ]
              ]
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            58 => array:3 [
              "identificador" => "bib0295"
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                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of gemcitabine and 2&#8217;&#44;2&#8217;-difluorodeoxyuridine in a patient with ascites"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:8 [
                        "tituloSerie" => "Pharmacotherapy"
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                        "volumen" => "20"
                        "numero" => "10"
                        "paginaInicial" => "1204"
                        "paginaFinal" => "1207"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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                        "itemHostRev" => array:3 [
                          "pii" => "S0022534710002569"
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                          "issn" => "00225347"
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            59 => array:3 [
              "identificador" => "bib0300"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fatal cholestatic liver failure associated with gemcitabine therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Dig Dis Sci"
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                        "volumen" => "48"
                        "numero" => "9"
                        "paginaInicial" => "1804"
                        "paginaFinal" => "1808"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            60 => array:3 [
              "identificador" => "bib0305"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:1 [
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                        "tituloSerie" => "JOP"
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                        "numero" => "4"
                        "paginaInicial" => "460"
                        "paginaFinal" => "467"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            61 => array:3 [
              "identificador" => "bib0310"
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                0 => array:2 [
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                      "titulo" => "Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction&#58; Cancer and Leukemia Group B 9565"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                    0 => array:2 [
                      "doi" => "10.1200/JCO.2000.18.14.2780"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
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                        "volumen" => "18"
                        "numero" => "14"
                        "paginaInicial" => "2780"
                        "paginaFinal" => "2787"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              "identificador" => "bib0315"
              "etiqueta" => "63&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic veno-occlusive disease due to DTIC"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
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                    0 => array:2 [
                      "doi" => "10.1002/1097-0142(19800515)45:10<2670::aid-cncr2820451031>3.0.co;2-l"
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                        "tituloSerie" => "Cancer"
                        "fecha" => "1980"
                        "volumen" => "45"
                        "numero" => "10"
                        "paginaInicial" => "2670"
                        "paginaFinal" => "2674"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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            63 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa020461"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2002"
                        "volumen" => "347"
                        "numero" => "7"
                        "paginaInicial" => "472"
                        "paginaFinal" => "480"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                    ]
                  ]
                ]
              ]
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            64 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "65&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib&#58; randomised trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(04)17098-0"
                      "Revista" => array:8 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2004"
                        "volumen" => "364"
                        "numero" => "9440"
                        "paginaInicial" => "1127"
                        "paginaFinal" => "1134"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283814012354"
                          "estado" => "S300"
                          "issn" => "03022838"
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                  ]
                ]
              ]
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            65 => array:3 [
              "identificador" => "bib0330"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Imatinib mesylate &#40;gleevec&#41; hepatotoxicity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10620-006-9117-1"
                      "Revista" => array:7 [
                        "tituloSerie" => "Dig Dis Sci"
                        "fecha" => "2007"
                        "volumen" => "52"
                        "numero" => "2"
                        "paginaInicial" => "598"
                        "paginaFinal" => "601"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              "identificador" => "bib0335"
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                0 => array:1 [
                  "referenciaCompleta" => "Miller AA&#44; Murray DJ&#44; Owzar K&#46; Pharmakokinetic &#40;PK&#41; and phase I study of sorafenib &#40;S&#41; for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction &#40;HD or RD&#41;&#58; CALGB 60301&#46; 25&#44; abstr&#46; 3538 ed&#46; 2007&#46;"
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              ]
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            67 => array:3 [
              "identificador" => "bib0340"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Current progress in targeted therapy for colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/107327481001700102"
                      "Revista" => array:7 [
                        "tituloSerie" => "Cancer Control"
                        "fecha" => "2010"
                        "volumen" => "17"
                        "numero" => "1"
                        "paginaInicial" => "7"
                        "paginaFinal" => "15"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                    ]
                  ]
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              ]
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            68 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "69&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2007.14.7116"
                      "Revista" => array:8 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2008"
                        "volumen" => "26"
                        "numero" => "10"
                        "paginaInicial" => "1626"
                        "paginaFinal" => "1634"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0022534709011720"
                          "estado" => "S300"
                          "issn" => "00225347"
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                  ]
                ]
              ]
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            69 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "70&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Fluorouracil&#44; leucovorin&#44; and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2008.20.8397"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2009"
                        "volumen" => "27"
                        "numero" => "5"
                        "paginaInicial" => "663"
                        "paginaFinal" => "671"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
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                  ]
                ]
              ]
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              "identificador" => "bib0355"
              "etiqueta" => "71&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A randomized phase IIIB trial of chemotherapy&#44; bevacizumab&#44; and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2008.19.8135"
                      "Revista" => array:8 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2009"
                        "volumen" => "27"
                        "numero" => "5"
                        "paginaInicial" => "672"
                        "paginaFinal" => "680"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S030228381201531X"
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                          "issn" => "03022838"
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                  ]
                ]
              ]
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            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effective second-line treatment with cetuximab and bevacizumab in a patient with hepatic metastases of colorectal cancer and hyperbilirubinemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000106098"
                      "Revista" => array:8 [
                        "tituloSerie" => "Onkologie"
                        "fecha" => "2007"
                        "volumen" => "30"
                        "numero" => "10"
                        "paginaInicial" => "509"
                        "paginaFinal" => "512"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                        "itemHostRev" => array:3 [
                          "pii" => "S0302283812014364"
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                          "issn" => "03022838"
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            72 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "73&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic injury associated with bevacizumab use in metastatic breast and colon cancers&#58; a review of two cases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Commun Oncol"
                        "fecha" => "2008"
                        "volumen" => "5"
                        "paginaInicial" => "539"
                        "paginaFinal" => "542"
                      ]
                    ]
                  ]
                ]
              ]
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            73 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "74&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX&#47;FOLFOX therapy of colorectal cancer liver metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ejso.2008.12.013"
                      "Revista" => array:7 [
                        "tituloSerie" => "Eur J Surg Oncol"
                        "fecha" => "2009"
                        "volumen" => "35"
                        "numero" => "5"
                        "paginaInicial" => "515"
                        "paginaFinal" => "520"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                    ]
                  ]
                ]
              ]
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            74 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "75&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Sinusoidal obstruction syndrome &#40;venoocclusive disease&#41; in a patient receiving bevacizumab for metastatic colorectal cancer&#58; a case report"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
                        "fecha" => "2007"
                        "volumen" => "2"
                        "paginaInicial" => "227"
                        "itemHostRev" => array:3 [
                          "pii" => "S0022534710037791"
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                          "issn" => "00225347"
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              "identificador" => "bib0380"
              "etiqueta" => "76&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Neoadjuvant chemotherapy for metastatic colon cancer&#58; a cautionary note"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2005.03.2334"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2005"
                        "volumen" => "23"
                        "numero" => "36"
                        "paginaInicial" => "9073"
                        "paginaFinal" => "9078"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              "identificador" => "bib0385"
              "etiqueta" => "77&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.sla.0000193603.26265.c3"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ann Surg"
                        "fecha" => "2006"
                        "volumen" => "243"
                        "numero" => "1"
                        "paginaInicial" => "1"
                        "paginaFinal" => "7"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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            77 => array:3 [
              "identificador" => "bib0390"
              "etiqueta" => "78&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Trends in long-term survival following liver resection for hepatic colorectal metastases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/00000658-200206000-00002"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ann Surg"
                        "fecha" => "2002"
                        "volumen" => "235"
                        "numero" => "6"
                        "paginaInicial" => "759"
                        "paginaFinal" => "766"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              ]
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              "identificador" => "bib0395"
              "etiqueta" => "79&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemotherapy prior to hepatic resection for colorectal liver metastases&#58; helpful until harmful&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000184733"
                      "Revista" => array:7 [
                        "tituloSerie" => "Dig Surg"
                        "fecha" => "2008"
                        "volumen" => "25"
                        "numero" => "6"
                        "paginaInicial" => "421"
                        "paginaFinal" => "429"
                        "link" => array:1 [
                          0 => array:2 [ …2]
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              ]
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            79 => array:3 [
              "identificador" => "bib0400"
              "etiqueta" => "80&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
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                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Chemother Rep"
                        "fecha" => "1975"
                        "volumen" => "59"
                        "paginaInicial" => "647"
                        "paginaFinal" => "659"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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              "identificador" => "bib0405"
              "etiqueta" => "81&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Chemotherapy dosing in the setting of liver dysfunction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Oncology &#40;Williston Park&#41;"
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                        "volumen" => "19"
                        "paginaInicial" => "1057"
                        "paginaFinal" => "1063"
                      ]
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                ]
              ]
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            81 => array:3 [
              "identificador" => "bib0410"
              "etiqueta" => "82&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic injury during doxorubicin therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Pathol Lab Med"
                        "fecha" => "1984"
                        "volumen" => "108"
                        "paginaInicial" => "912"
                        "paginaFinal" => "913"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            82 => array:3 [
              "identificador" => "bib0415"
              "etiqueta" => "83&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacokinetics of anticancer agents in patients with impaired liver function"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Cancer"
                        "fecha" => "1998"
                        "volumen" => "34"
                        "paginaInicial" => "33"
                        "paginaFinal" => "46"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                ]
              ]
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            83 => array:3 [
              "identificador" => "bib0420"
              "etiqueta" => "84&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Predicting etoposide toxicity&#58; relationship to organ function and protein binding"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.1996.14.1.257"
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                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "1996"
                        "volumen" => "14"
                        "paginaInicial" => "257"
                        "paginaFinal" => "267"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                          "pii" => "S0022534713061090"
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                          "issn" => "00225347"
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            84 => array:3 [
              "identificador" => "bib0425"
              "etiqueta" => "85&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Veno-occlusive disease of the liver after hemopoietic cell transplatnation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [ …1]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Haematol"
                        "fecha" => "2000"
                        "volumen" => "64"
                        "paginaInicial" => "281"
                        "paginaFinal" => "291"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
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                  ]
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              ]
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            85 => array:3 [
              "identificador" => "bib0430"
              "etiqueta" => "86&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Etosposid &#40;VP 16-213&#41; induced hepatitis&#46; Report of three cases following standard-dose treatments"
                      "autores" => array:1 [
                        0 => array:2 [
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Article information

ISSN: 16652681
Original language: English

DOI:10.1016/S1665-2681(19)31651-5

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Year/Month	Html	Pdf	Total

2024 November	88	0	88
2024 October	2496	64	2560
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2024 August	2840	69	2909
2024 July	3139	76	3215
2024 June	2150	55	2205
2024 May	2323	50	2373
2024 April	2661	66	2727
2024 March	2730	54	2784
2024 February	2924	88	3012
2024 January	3192	121	3313
2023 December	2691	106	2797
2023 November	2563	93	2656
2023 October	2463	94	2557
2023 September	2370	68	2438
2023 August	2019	80	2099
2023 July	1758	53	1811
2023 June	1576	56	1632
2023 May	1739	66	1805
2023 April	1497	57	1554
2023 March	1195	69	1264
2023 February	881	50	931
2023 January	815	46	861
2022 December	718	37	755
2022 November	972	59	1031
2022 October	873	67	940
2022 September	773	54	827
2022 August	827	48	875
2022 July	677	43	720
2022 June	607	54	661
2022 May	592	58	650
2022 April	583	82	665
2022 March	595	87	682
2022 February	590	47	637
2022 January	476	49	525
2021 December	423	68	491
2021 November	459	81	540
2021 October	514	70	584
2021 September	440	65	505
2021 August	479	37	516
2021 July	492	38	530
2021 June	531	64	595
2021 May	504	67	571
2021 April	1218	157	1375
2021 March	622	76	698
2021 February	409	66	475
2021 January	308	44	352
2020 December	283	39	322
2020 November	277	45	322
2020 October	202	20	222
2020 September	158	18	176
2020 August	157	25	182
2020 July	92	26	118
2020 June	84	15	99
2020 May	89	16	105
2020 April	75	22	97
2020 March	48	8	56
2020 February	34	16	50
2020 January	26	6	32
2019 December	15	8	23
2019 November	9	4	13
2019 October	8	3	11
2019 September	6	2	8
2019 August	2	1	3
2019 July	2	5	7

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