Review
Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100mg/m2 seems sufficient
Tratamiento exitoso con una dosis elevada y adaptada de metotrexato en una paciente de hemodiálisis con linfoma primario del sistema nervioso central: 100 mg/m2 parece suficiente
Justine Solignaca,b, Laure Farnaultc, Thomas Roberta, Raphaelle Fanciullinod, Sylvain Choquete, Philippe Bruneta,b, Geoffroy Ventonc,f, Mickaël Bobota,b,
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a Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Assistance Publique – Hôpitaux de Marseille, Marseille, France
b C2VN, INSERM, INRAE, Aix Marseille Université, Marseille, France
c Service d’Hématologie et Thérapie Cellulaire, Hôpital de la Conception, Assistance Publique – Hôpitaux de Marseille, Marseille, France
d Laboratoire de Pharmacologie, Hôpital de La Timone, Assistance Publique – Hôpitaux de Marseille, Marseille, France
e Service d’Hématologie, Hôpital de la Pitié-Salpêtrière, Assistance-Publique – Hôpitaux de Paris, Paris, France
f TAGC, INSERM UMR 1090, Aix Marseille Université, Marseille, France
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[ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Assistance Publique – Hôpitaux de Marseille, Marseille, France" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "C2VN, INSERM, INRAE, Aix Marseille Université, Marseille, France" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Service d’Hématologie et Thérapie Cellulaire, Hôpital de la Conception, Assistance Publique – Hôpitaux de Marseille, Marseille, France" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Laboratoire de Pharmacologie, Hôpital de La Timone, Assistance Publique – Hôpitaux de Marseille, Marseille, France" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Service d’Hématologie, Hôpital de la Pitié-Salpêtrière, Assistance-Publique – Hôpitaux de Paris, Paris, France" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "TAGC, INSERM UMR 1090, Aix Marseille Université, Marseille, France" "etiqueta" => "f" "identificador" => "aff0030" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento exitoso con una dosis elevada y adaptada de metotrexato en una paciente de hemodiálisis con linfoma primario del sistema nervioso central: 100 mg/m<span class="elsevierStyleSup">2</span> parece suficiente" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2558 "Ancho" => 2175 "Tamanyo" => 185663 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Median [interquartile range] of plasma MTX concentration (μmol/L) following administration. Cycle 5 Days 15 was excluded. Small arrows represent dialysis sessions. The dashed line demarcates concentration at which folinic acid rescue was stopped. MTX: Methotrexate. MTXc: Methotrexate concentration.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">High-dose methotrexate (HD-MTX) is the cornerstone of the chemotherapy treatment of the primary central nervous system non-Hodgkin lymphoma (PCNSL).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Methotrexate is an antimetabolite interfering with the metabolism of folic acid, thereby blocking purine synthesis. HD-MTX defined by doses ≥500<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, most often from 1 to 4<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span>, are required to cross the blood–brain barrier and achieved therapeutic level in the central nervous system.</p><p id="par0010" class="elsevierStylePara elsevierViewall">MTX is mainly excreted by the kidneys, and delayed drug clearance may lead to toxicity.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Toxicity is dependent on both duration of complete elimination from the body and serum MTX concentration (MTXc). Therapy drug monitoring is mandatory to guide folinic acid rescue and prevent severe toxicities.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Because renal dysfunction conduces to delayed MTX complete elimination and critical MTXc, end-stage renal disease (ESRD) is considered as a contra-indication for HD-MTX.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nevertheless the drug is effectively cleared through hemodialysis,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> and drug monitoring is easily available. However, data is missing in these particular patients.</p><p id="par0025" class="elsevierStylePara elsevierViewall">We report a case of a hemodialysis patient with PCNSL successfully treated by 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> adjusted HD-MTX-based chemoimmunotherapy regimen.</p><p id="par0030" class="elsevierStylePara elsevierViewall">A 64-year-old woman ongoing chronic hemodialysis for 7 years for an unspecified nephropathy, presented a brutal right facial paralysis, right hemicorpus dysesthesia and balance disorders. The magnetic resonance imaging (MRI) identified a lesion affecting the brain bridge, the right middle cerebellar peduncle and cerebellar hemisphere (Supplementary Fig. 1a, b). A stereotactic biopsy confirmed the diagnosis of diffuse large B-cell lymphoma with no other location assessed by positron emission tomography (PET) scan, establishing the diagnosis of PCNSL. EBV serology was negative. After multidisciplinary discussion, accordingly to the previous published data,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> the patient received 28 cycles of chemotherapy regimen R-MPV (Protocol described in Supplementary Methods). We used an adjusted the dose of MTX at 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, based on the experience of one of the authors <span class="elsevierStyleItalic">(unpublished)</span>.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Dialysis procedures was started 24<span class="elsevierStyleHsp" style=""></span>h after MTX administration and conducted daily for four hours by predilution hemodiafiltration with high-flux dialyser, dialysate flow of 500<span class="elsevierStyleHsp" style=""></span>mL/min, blood flow of 250<span class="elsevierStyleHsp" style=""></span>mL/min, and high dialysate bicarbonate concentration (40<span class="elsevierStyleHsp" style=""></span>mmol/L). Daily dialysis was discontinued when MTXc was <<span class="elsevierStyleHsp" style=""></span>0.1<span class="elsevierStyleHsp" style=""></span>μmol/L.</p><p id="par0040" class="elsevierStylePara elsevierViewall">MTXc were measured before and after each dialysis session.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Median MTXc 24<span class="elsevierStyleHsp" style=""></span>h after infusion was 14 [9.6–15.0]<span class="elsevierStyleHsp" style=""></span>μmol/L (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). No rebound phenomenon was observed. MTX was completely cleared on average at 5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.6 days post-infusion.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Dose intensity was respected, and no course was delayed. Patient exhibited 2 episodes of undocumented sepsis with rapid favorable recovery, anemia requiring 2 red blood cells transfusion and mucositis.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Intermediary evaluation after 3 cycles with MRI assessment revealed a complete response.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The fifth cycle was marked by an unexplained MTX overdose at 180<span class="elsevierStyleHsp" style=""></span>μmol/L 24<span class="elsevierStyleHsp" style=""></span>h after administration, without clinical nor biological toxicity. The patient had an extended hemodialysis session of 16<span class="elsevierStyleHsp" style=""></span>h in intensive care unit, achieving MTXc<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.5<span class="elsevierStyleHsp" style=""></span>μmol/L and <0.1<span class="elsevierStyleHsp" style=""></span>μmol/L after 1 more dialysis.</p><p id="par0065" class="elsevierStylePara elsevierViewall">We thus decided to stop the chemotherapy treatment after 5 cycles, given the persistent complete response on MRI (Supplementary Fig. 1c, d) and brain PET-scan.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The patient is actually still in complete remission at 1 year.</p><p id="par0075" class="elsevierStylePara elsevierViewall">We report here the feasibility of HD-MTX-like therapy in hemodialysis patients, and the first use of a dose divided by more than 10 from the standard dose. Herein, with an adjusted dose at 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, with first hemodialysis session, our patient reached the expected MTXc at H24 and treatment was well tolerated with no significant toxicity and efficient with total recovery.</p><p id="par0080" class="elsevierStylePara elsevierViewall">PCNSL is an aggressive type of lymphoma with a rapidly fatal course in the absence of treatment. HD-MTX-based chemoimmunotherapy have been shown to improve survival, even in elderly patients, and is a central part of the standard approach to treatment.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">2,4</span></a> Avoiding HD-MTX in hemodialysis patients leads to a loss of chance.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Although its important protein-binding and low distribution volume, 63% of MTX infused can be removed after a 6<span class="elsevierStyleHsp" style=""></span>h high-flux hemodialysis session, four-fold faster than renal excretion.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The strict monitoring of residual MTXc represents the major point for limiting its toxicity while keeping its effectiveness.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Five cases about HD-MTX use in hemodialysis patients have been reported (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">3,5–8</span></a> The doses used were the same as in the general population (1–4<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span>). Some authors performed daily high-flux hemodialysis 24<span class="elsevierStyleHsp" style=""></span>h after MTX infusion: cMTX were then very high (>20<span class="elsevierStyleHsp" style=""></span>μmol/L) after the first dialysis session,<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6–8</span></a> above the threshold of toxicity.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> In any case, MTX was completely eliminated within 5–7 days after infusion.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Importantly, we used a dose of 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> every 2 weeks, and cMTX were close to those described in non-ESRD patients with PCNSL treated by HD-MTX.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4,9</span></a> Our patient had moderate and reversible MTX-induced toxicity, and favorable outcome. ESRD patients may also have an increased efficacy of MTX at lower doses, due to a potentially increased blood-brain barrier permeability.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> as a viable therapeutic modality in ESRD patients.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Statement of ethics</span><p id="par0110" class="elsevierStylePara elsevierViewall">The patient gave her informed consent for the publication of this case report.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Funding sources</span><p id="par0115" class="elsevierStylePara elsevierViewall">None.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres1740779" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1535305" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1740778" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1535304" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Statement of ethics" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Funding sources" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Conflict of interest" ] 7 => array:2 [ "identificador" => "xack614934" "titulo" => "Acknowledgements" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-01-28" "fechaAceptado" => "2021-03-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1535305" "palabras" => array:5 [ 0 => "Methotrexate" 1 => "Central nervous system" 2 => "Lymphoma" 3 => "Hemodialysis" 4 => "Drug toxicity" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1535304" "palabras" => array:5 [ 0 => "Metotrexato" 1 => "Sistema nervioso central" 2 => "Linfoma" 3 => "Hemodiálisis" 4 => "Toxicidad farmacológica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, instead of the usual dose of 3500<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span>, and daily hemodialysis started 24<span class="elsevierStyleHsp" style=""></span>h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100<span class="elsevierStyleHsp" style=""></span>mg/m<span class="elsevierStyleSup">2</span> as a viable therapeutic modality in ESRD patients.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La quimioinmunoterapia basada en una dosis elevada de metotrexato (HD-MTX) es una parte central del enfoque terapéutico estándar del linfoma primario del sistema nervioso central (PCNSL). La insuficiencia renal causa la demora de la eliminación completa de MTX, así como la concentración crítica del mismo. A pesar de las recomendaciones, el estatus de hemodiálisis no debería excluir la HD-MTX.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Reportamos el caso de una mujer de 64 años con PCNSL y tratamiento de hemodiálisis crónica que fue exitosamente tratada con quimioinmunoterapia basada en HD-MTX con una dosis ajustada de 100 mg/m<span class="elsevierStyleSup">2</span>, en lugar de la dosis habitual de 3.500 mg/m<span class="elsevierStyleSup">2</span>, iniciándose la hemodiálisis diaria al cabo de 24 h. La paciente no reflejó toxicidad significativa y experimentó remisión completa al cabo de un año desde la finalización del tratamiento.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Nosotros argumentamos que la enfermedad renal en etapa terminal (ESRD) no constituye un escollo en absoluto para utilizar la HD-MTX para neoplasias hematológicas. Los expertos deberían considerar el uso de una dosis ajustada a 100 mg/m<span class="elsevierStyleSup">2</span> como modalidad terapéutica viable en los pacientes de ESRD.</p></span>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2558 "Ancho" => 2175 "Tamanyo" => 185663 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Median [interquartile range] of plasma MTX concentration (μmol/L) following administration. Cycle 5 Days 15 was excluded. Small arrows represent dialysis sessions. The dashed line demarcates concentration at which folinic acid rescue was stopped. MTX: Methotrexate. MTXc: Methotrexate concentration.</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:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">CMV: cytomegalovirus, HD: hemodialysis, HD-MTX: high dose methotrexate, PCNSL: primary central nervous system non Hodgkin lymphoma, PTLD: post-transplantation lymphoproliferative disorder, y.o.: years old.</p>" "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex and age \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose of MTX \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type and duration of HD \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Time to HD initiation after infusion (h) \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MTX plasma concentration 24<span class="elsevierStyleHsp" style=""></span>h after the first infusion (μmol/l) \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patient evolution \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wall et al., 1996 \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="\n \t\t\t\t\ttop\n \t\t\t\t">F13 y.o. \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="\n \t\t\t\t\ttop\n \t\t\t\t">Osteosarcoma \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="\n \t\t\t\t\ttop\n \t\t\t\t">7.2<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> \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="\n \t\t\t\t\ttop\n \t\t\t\t">High flux6<span class="elsevierStyleHsp" style=""></span>h \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150 \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="\n \t\t\t\t\ttop\n \t\t\t\t">Not specified \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mutsando et al., 2012 \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="\n \t\t\t\t\ttop\n \t\t\t\t">F52 y.o. \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="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral PTLD \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="\n \t\t\t\t\ttop\n \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> and escalating dose \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="\n \t\t\t\t\ttop\n \t\t\t\t">High flux7<span class="elsevierStyleHsp" style=""></span>h \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">Pancytopenia, gastrointestinal and hepatic toxicity, invasive infection with endocarditis.Death 4 month after 2 doses treatment from a CMV related perforated gastric ulcer. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Murashima et al., 2009 \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="\n \t\t\t\t\ttop\n \t\t\t\t">M58 y.o. \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="\n \t\t\t\t\ttop\n \t\t\t\t">PCNSL \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="\n \t\t\t\t\ttop\n \t\t\t\t">C1 3<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span>C2 6<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span>then 4<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> \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="\n \t\t\t\t\ttop\n \t\t\t\t">High flux6<span class="elsevierStyleHsp" style=""></span>h \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \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="\n \t\t\t\t\ttop\n \t\t\t\t">Not specified \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reshetenik et al., 2015 \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="\n \t\t\t\t\ttop\n \t\t\t\t">M26 y.o. \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="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral PTLD (second line) \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="\n \t\t\t\t\ttop\n \t\t\t\t">4<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> \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="\n \t\t\t\t\ttop\n \t\t\t\t">High flux4<span class="elsevierStyleHsp" style=""></span>h \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 \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="\n \t\t\t\t\ttop\n \t\t\t\t">Severe CMV and E.coli pneumonia requiring invasive ventilation and leading to stop chemotherapy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yeung et al., 2019 \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="\n \t\t\t\t\ttop\n \t\t\t\t">M41 y.o. \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="\n \t\t\t\t\ttop\n \t\t\t\t">Cerebral PTLD \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="\n \t\t\t\t\ttop\n \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g/m<span class="elsevierStyleSup">2</span> and escalating dose \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="\n \t\t\t\t\ttop\n \t\t\t\t">High flux8<span class="elsevierStyleHsp" style=""></span>h \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 \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="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical remission at 1 year after treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Previously published cases of hemodialysis patients treated by HD-MTX.</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" => "Advances and challenges in the treatment of primary central nervous system lymphoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H. 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