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Chemotherapy-induced enteritis: Institutional experience and review of the literature
Enteritis inducida por quimioterapia: experiencia institucional y revisión bibliográfica
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La TC muestra el engrosamiento mural concéntrico circunferencial difuso del íleon, que incluye el íleo terminal (flecha negra) (el ciego está señalado con un asterisco negro; la válvula ileocecal está señalada con un asterisco blanco).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Almagro Casado, L. Gutierrez, A.C. Sánchez Ruiz, A. Ruiz Casado" "autores" => array:4 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Almagro Casado" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Gutierrez" ] 2 => array:2 [ "nombre" => "A.C." "apellidos" => "Sánchez Ruiz" ] 3 => array:2 [ "nombre" => "A." 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Almagro Casado, L. Gutierrez, A.C. Sánchez Ruiz, A. Ruiz Casado" "autores" => array:4 [ 0 => array:4 [ "nombre" => "E." "apellidos" => "Almagro Casado" "email" => array:1 [ 0 => "e.almagro.c@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "L." "apellidos" => "Gutierrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "A.C." "apellidos" => "Sánchez Ruiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "A." "apellidos" => "Ruiz Casado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario Quironsalud Madrid, Pozuelo de Alarcón, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Enteritis inducida por quimioterapia: experiencia institucional y revisión bibliográfica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 758 "Ancho" => 900 "Tamanyo" => 72737 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patient 2. Computed tomography shows diffuse circumferential concentric thickening of the ileum wall, which includes terminal ileum (black arrow) (the blind loop is indicated by a black asterisk; the ileocecal valve is indicated by a white asterisk).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Abdominal pain is a standard emergency in patients treated with chemotherapy. When faced with this symptom, the main diseases that should be ruled out are acute abdomen and typhlitis. In the absence of neutropenia and other signs of severe illness, however, other causes for the abdominal pain should be considered. Better access to computed tomography images in the emergency department could expose the fact that some cases of intestinal toxicity have been overlooked. Small bowel toxicity secondary to chemotherapy has been considered a rare secondary effect associated with fluoropyrimidine agents. Enteritis or, more commonly, ileitis, which is considered an anecdotal finding and has been reported only in individual cases,<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1–8</span></a> could be not so exceptional.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this article, we present 5 cases of patients with gastrointestinal tumors who developed chemotherapy-induced enteritis after being administered various regimens that contained fluoropyrimidine agents (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). On admission, all of them presented severe abdominal pain and abnormal laboratory results, with the CT revealing intestinal wall thickening (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Other symptoms included diarrhea and, to a lesser extent, nausea and fever. The patients presented hypoalbuminemia and coagulopathy, resembling protein-losing enteropathy. Both leukocytosis and leukopenia were found in the patients. Only one patient presented neutropenia at the time of the diagnosis, and the episode was short.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The main cause of ileitis is Crohn's disease. There is, however, a considerable variety of disease processes that are associated with this condition, including infections, nodular lymphoid hyperplasia and tumors. Surprisingly, chemotherapy is not among the causes of ileitis. The diagnosis of chemotherapy-induced ileitis is performed with imaging techniques, with CT employed most often due to its availability in emergency departments. The main reason patients visit the hospital is for abdominal pain. Colonoscopy can reveal the presence of ulcers.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1,3,5</span></a> Typhlitis should be considered in the differential diagnosis of abdominal pain for a patient undergoing chemotherapy.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Fluoropyrimidine agents, such as 5-fluorouracil (5-FU) or its prodrug, capecitabine, have been widely used in treating gastrointestinal cancer. The most common adverse effects of 5-FU are diarrhea and oral mucositis. Gastrointestinal mucosal impairment can allow microorganisms to enter the bloodstream, thereby causing sepsis, especially if it occurs during the nadir of chemotherapy. This is why broad-spectrum antibiotics are employed for these situations. Some patients can present small bowel perforation, which requires a surgical approach.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Enteritis is an uncommon but well-known adverse effect of capecitabine.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Fata et al. published their experience (6 cases) with the classical regimen of 5-FU (5-FU in bolus),<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> while Mokrim et al.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> and Lee et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> reviewed the literature on ileitis secondary to capecitabine (6 and 2 cases, respectively).</p><p id="par0025" class="elsevierStylePara elsevierViewall">Only 1 patient in our series underwent a regimen of irinotecan with FOLFIRINOX. Although this drug is known to cause early (acetylcholinesterase-mediated) and late onset diarrhea, its contribution to chemotherapy-induced diarrhea is less known. Two patients were administered bevacizumab as part of their therapy. To date, an association between this antivascular endothelial growth factor and enteritis has not been reported; however, it is difficult to determine this drug's contribution to gastrointestinal mucosal damage in the context of the combination with irinotecan or fluoropyrimidine agents. Angiogenesis inhibition could influence the healing process after mucosal damage.</p><p id="par0030" class="elsevierStylePara elsevierViewall">It appears that chemotherapy-induced enteritis is more common in the early stages of first-line/adjuvant chemotherapy and in right colon tumors. Ileitis would also be more common with capecitabine<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> and with 5-FU in bolus than with 5-FU in continuous infusion. An option would therefore be to change from bolus to continuous infusion. A number of authors have reported ulcers in the ileus, appearing in normal colons during colonoscopy,<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,4,6</span></a> with the pathological corollary being apoptotic enteropathy.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> These histological changes resemble graft-versus-host disease for intestinal transplantation or mycophenolate-induced colonopathy. Protein kinase C activation would lead to contraction of the vascular smooth muscle (vasoconstriction).</p><p id="par0035" class="elsevierStylePara elsevierViewall">Management for these patients is essentially that of support. As part of the treatment, we have fluid resuscitation therapy, corticosteroids and the empiric use of broad-spectrum antibiotics. Surgery is not contemplated except in the event of intestinal perforation. Fluoropyrimidine agents may be reintroduced, depending on the severity of the event.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Dosage reductions may also be considered.</p><p id="par0040" class="elsevierStylePara elsevierViewall">To summarize, chemotherapy-induced enteritis is not a rare disease. Oncologists, surgeons and emergency department physicians should consider this condition when dealing with the presence of abdominal pain, diarrhea, hypoalbuminemia and hypoprothrombinemia. A lack of lasting neutropenia preceding the condition does not favor the diagnostic of typhlitis. In the absence of typhlitis, surgery is unnecessary, and patients generally progress well with supportive therapy. As recorded in our study and in other series, the onset of ileitis does not preclude the administration of the suspected agent in successive cycles.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Almagro Casado E, Gutierrez L, Sánchez Ruiz AC, Ruiz Casado A. Enteritis inducida por quimioterapia: experiencia institucional y revisión bibliográfica. Rev Clin Esp. 2019;219:165–167.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 758 "Ancho" => 900 "Tamanyo" => 72737 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patient 2. Computed tomography shows diffuse circumferential concentric thickening of the ileum wall, which includes terminal ileum (black arrow) (the blind loop is indicated by a black asterisk; the ileocecal valve is indicated by a white asterisk).</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Primary tumor \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Stage at diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Chemotherapy regimen \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cycle in which toxicity appeared \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Symptoms \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormal laboratory results \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Affected intestine \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Retreatment after the toxic episode \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dosage adjustment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recurrence of toxicity \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Alive after the episode \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Case 1 (64a) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Colon (appendix-blind loop) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">XELOX BEVACIZUMAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diarrhea, abdominal pain, oral intolerance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoalbuminemia 2.4<span class="elsevierStyleHsp" style=""></span>mg/dL<br>Prothrombin activity, 86%<br>CRP >250 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ileum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Change to FOLFOX 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Case 2 (76a) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Colon (sigma) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">XELOX BEVACIZUMAB \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diarrhea, fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoalbuminemia, 2.9<span class="elsevierStyleHsp" style=""></span>mg/dL<br>Prothrombin activity 54%<br>Hypocalcemia, 3.2<span class="elsevierStyleHsp" style=""></span>mmol/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ileum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes<br>50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Case 3 (73a) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Colon (transversus) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FOLFOX 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Abdominal distension and pain, vomiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoalbuminemia, 3.3<span class="elsevierStyleHsp" style=""></span>mg/dL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ileum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes<br>20% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Case 4 (71a) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pancreas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FOLFIRINOX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fever, abdominal pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoalbuminemia, 2.9<span class="elsevierStyleHsp" style=""></span>mg/dL<br>Prothrombin activity, 62%<br>Hypocalcemia, 3.0<span class="elsevierStyleHsp" style=""></span>mmol/L<br>Neutropenia, 400 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Jejunum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes<br>75% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Case 5 (77a) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Colon (blind loop) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CAPECITABINE adjuvant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diarrhea, abdominal pain, proctorrhagia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypoalbuminemia, 3.0<span class="elsevierStyleHsp" style=""></span>mg/dL<br>Prothrombin activity, 49%<br>Hypocalcemia, 2.4<span class="elsevierStyleHsp" style=""></span>mmol/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ulcerative ileitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Suspension of adjuvant therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1999367.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Institutional experience.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0055" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "5-Fluorouracil-induced small bowel toxicity in patients with colorectal carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "F. 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