Light chain amyloidosis: Experience in a tertiary hospital: 2005–2013

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Krsnik, M. Cabero, D. Morillo, J. Segovia, P. García-Pavía, M. Gómez-Bueno, C. Salas" "autores" => array:7 [ 0 => array:4 [ "nombre" => "I." "apellidos" => "Krsnik" "email" => array:1 [ 0 => "isabel.krsnik@salud.madrid.org" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Cabero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "D." "apellidos" => "Morillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "J." "apellidos" => "Segovia" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "P." 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"apellidos" => "Salas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Cardiología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Amiloidosis de cadenas ligeras: experiencia en un hospital terciario 2005–2013" ] ] "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" => 1070 "Ancho" => 1202 "Tamanyo" => 89240 ] ] "descripcion" => array:1 [ "en" => "Serum immunochemistry results. FLC: free light chains." ] ] ] "textoCompleto" => "<elsevierMultimedia ident="tb0005"></elsevierMultimedia>BackgroundAmyloidosis is a heterogeneous group of rare diseases caused by the deposit of amyloid fibrils in tissue, which can be demonstrated through Congo red staining. Some 30 proteins with amyloidogenic capacity have been described. The use of the protein's abbreviation in the nomenclature is recommended to avoid confusing terms such as primary, secondary, systemic and localized.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>In light-chain amyloidosis (AL, the most common form of amyloidosis), light chains of degraded monoclonal immunoglobulins are deposited, which are always produced by a neoplasm of lymphoproliferative origin.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Patients usually report highly nonspecific symptoms, which delays the diagnosis. More than a third of patients start with serious impairment of various organs. In recent years, there have been significant developments in the diagnosis and treatment of patients with AL amyloidosis. These advances include the measurement of the amino-terminal fragment of the brain natriuretic peptide (NT-proBNP) and the use of magnetic resonance imaging (MRI) to assess cardiac impairment.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> The quantification of serum free light chains (FLCs) of immunoglobulins can provide the basis for suspecting the presence of an underlying neoplasm of lymphoproliferative origin, which can advance the diagnosis and help monitor the treatment.<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a> From the therapeutic point of view, another advance is the emergence of bortezomib, a proteasome inhibitor that improves organ impairment.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Risk stratification of patients<a class="elsevierStyleCrossRefs" href="#bib0025">5,10</a> helps when making therapeutic decisions and when using the most rational modalities such as autologous bone marrow transplantation (ABMT) and heart transplantation (HTx).The aim of this study is to describe a contemporary series of patients with AL amyloidosis to analyze the issues that could contribute to an earlier diagnosis and optimal management, with special mention of the therapeutic options available in our community.Patients and methodsPatientsOur series included 32 consecutive patients treated at the Department of Hematology of the University Hospital Puerta de Hierro, Majadahonda (Madrid, Spain) between 2005 and 2013 who had an unequivocal histological diagnosis of AL amyloidosis. To this end, we required deposits of amyloid material that stained positive for Congo red in tissue and the demonstration of monoclonality using immunoglobulin light chain antibodies (immunohistochemistry [IHC]). In cases in which the IHC of the amyloid tissue did not show monoclonality, we required the presence of amyloids in the bone marrow (BM) or cardiac biopsy, after specifically ruling out the deposit of other proteins such as transthyretin (TTR).<a class="elsevierStyleCrossRefs" href="#bib0005">1,11</a>The patients were studied and treated according to the healthcare protocols of the Departments of Hematology and Cardiology, and the patients gave their informed consent to participate in the study. The data collection and the preparation of this article were approved by the Ethics Committee of the University Hospital Puerta de Hierro and comply with the specifications of the Declaration of Helsinki.Additional studiesClinical, laboratory and BM biopsy data were collected prospectively by the Department of Hematology. The results of the cardiac imaging tests and endomyocardial biopsies were analyzed retrospectively. The clinical data included demographic data, general condition (Eastern Cooperative Oncology Group [ECOG] scale),<a class="elsevierStyleCrossRef" href="#bib0060">12</a> clinical involvement of organs and systems, treatment received and treatment response, survival as of January 1, 2014, and, if necessary, cause of death.All laboratory tests and tissue stainings were performed using standard, commercially available techniques. The tests performed in serum were protein electrophoresis in agarose gel, immunofixation (IF) using specific antibodies against light and heavy chains, immunoglobulin and FLC quantification through nephelometry and measurement of NT-proBNP. Protein quantification, electrophoresis and IF were performed in urine.Biopsies were performed on organs and tissue that had indications of clinical involvement or that had therapeutic or prognostic relevance, except for the biopsies of saliva glands and fat, which were performed for diagnostic purposes, and the BM biopsies, which were performed by protocol for all patients.The BM study included an aspirate with counts of the various series and a biopsy with IHC (quantification of plasma cells after staining with anti-CD138, anti-CD56, anti-κ and anti-λ). In other tissues, the presence of amyloid material was determined with the Congo red and thioflavin staining technique. The characterization of the material was performed using specific antisera against light κ and λ immunoglobulin chains. For the cardiac biopsies with amyloid deposits, stainings were performed for TTR, amyloid A and amyloid P component (IHC). The cardiac biopsies performed in other centers were reviewed in our hospital.The cardiac assessment included a transthoracic echocardiogram and/or MRI with gadolinium. In 25 cases (80%), cardiac scintigraphy with 99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid (99mTC-DPD) was performed.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> This study was not performed in 7 cases due to early death (5 cases) and logistical problems (2 cases).Assessment of therapeutic responseThe response (in terms of laboratory tests and clinical involvement of organs) was assessed according to recently published guidelines.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Complete hematologic response was defined as the normalization of FLCs with negative IF in serum and urine. A reduction to <40mg/L of the difference between affected and unaffected FLCs was considered a very good partial response. Cardiac response was defined as a >30% reduction in NT-proBNP levels and levels >300ng/L in cases with baseline levels >650ng/L. Renal response required a 50% reduction in proteinuria (minimum of 0.5g/day), with stable renal function.ResultsClinical involvement and additional examinations<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the demographic and clinical data at the time of diagnosis.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><a class="elsevierStyleCrossRef" href="#tbl0015">Table 2</a> shows the clinical involvement of organs and systems over the patients’ evolution, from their diagnosis to the date of death or to January 1, 2014, the date when the data collection was closed. <a class="elsevierStyleCrossRef" href="#tbl0025">Table 3</a> shows the results of the biopsies. In terms of the immunochemistry studies, 19 cases showed a monoclonal component in serum and 8 showed abnormal FLC values with no monoclonal component. In 5 cases that showed no monoclonal component, the FLCs were not measured (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Twenty-four of the 32 cases showed a monoclonal component in urine. Overall, 31/32 cases showed abnormal immunochemical data, either in serum or in urine. FLCs could not be measured in 1 case with negative IF in serum and urine (the technique was not available at the time), and the diagnosis was conducted by IHC analysis of the amyloid. The clonality of the light chain demonstrated in BM/serum/urine or the IHC analysis of the amyloid was λ in 25 cases and κ in 7 cases.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia>The BM studies showed a population of plasma cells with clonality equal to that of the serum/urine in 29 cases (90%); 10 cases with infiltration <10% and 19 with infiltration ≥10%. One case showed no excess of monoclonal plasma cells in the BM; however, an excess was evident in the skin in the form of a plasmacytoma accompanied by amyloid material. Two cases showed infiltration of the BM by a low-grade CD20-positive B-cell lymphoproliferative syndrome (LPS). None of the 25 scintigraphy studies performed with 99mTC-DPD showed biventricular uptake in the cardiac area (visual score 0–1).Treatment and responseTen patients did not undergo treatment; 8 due to early exitus (median survival after diagnosis, 30 days), 1 due to absence of indication (AL amyloidosis with cutaneous plasmacytoma) and 1 for previous disabling stroke. Another recently diagnosed case was excluded from the analysis because the patient had just started treatment.<a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a> shows the treatments undergone and the hematologic and organ response of the 21 treated patients. Twelve of these patients were treated with combinations of bortezomib (with alkylating agents, steroids or both), 5 patients were treated with alkylating agents plus steroids, and 1 was treated with rituximab and cyclophosphamide (CD20+ SLP). One patient underwent an HTx immediately after the diagnosis with no previous treatment and then subsequently underwent an ABMT. Two patients underwent ABMT without prior treatment.<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>Fourteen patients were treated with high doses of bortezomib and/or melphalan as conditioning for ABMT, and of these, 12 achieved complete hematologic response. Of the 10 patients treated with bortezomib and/or ABMT and without HTx, 8 achieved organ response (1 died early and 1 has just completed treatment). Five patients treated with bortezomib combinations achieved cardiac response. Of these, 3 met cardiac criteria for HTx but were not included in the waiting lists due to rejection of the technique, lung impairment and age limit, respectively. The NT-proBNP levels began to descend in these 5 cases 4–6 months after starting the treatment. A patient in this group died 46 months after diagnosis following a stroke of embolic origin, having refused to undergo anticoagulant treatment. In the cases with nephrotic-range proteinuria, the protein levels in urine began to descend later (8–12 months after starting the treatment) and continued to descend for 2–3 years. The response of the affected organs after medical treatment could not be assessed for those patients who underwent a HTx. These 5 patients improved after the procedure, with an ECOG score of 0 at 3 months of the operation. All underwent antineoplastic treatment before and/or after the HTx. Three of these patients are still living (44, 47 and 60 months after the procedure), with an ECOG score of 0–1. We have observed no new amyloid deposits in the heart in any of the patients who underwent HTx, in whom 8–16 serial endomyocardial biopsies were performed during the first year.Of the 12 patients with NT-proBNP levels >8500ng/L at diagnosis, 3 who underwent a HTx and 1 who was treated with bortezomib in combination survived; the remaining 8 died in less than 6 months.The group of 14 surviving patients included 1 patient with a cutaneous plasmacytoma without indication for treatment at present, 3 with primarily renal impairment (nephrotic syndrome) and who underwent ABMT, 3 who underwent HTx and 5 with multiple organ involvement who have completed treatment. With the exception of 2 patients who underwent ABMT without prior antineoplastic treatment and one who has just begun treatment, the rest of the survivors were or are currently being treated with bortezomib in combination with alkylating agents and/or steroids (<a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a>).OutcomeThe median overall survival from diagnosis was 17 months (range: 1–98).Fourteen patients (43%) (median age, 59 years; range, 53–86 years) were still alive on January 1, 2014, with a median survival after diagnosis of 27.5 months (range, 5–98 months).Eighteen (56%) patients died, 13 of them due to heart failure and 2 due to acute rejection of the heart transplant; another 2 patients died from pneumonia and 1 died after a stroke.DiscussionIn this study, we described the clinical characteristics, diagnostic issues, assessment, evolution and treatment of a contemporary series of 32 patients with AL amyloidosis treated at a tertiary hospital in Spain. Our series adequately illustrates the clinical variability, diagnostic complexity and, especially, the multidisciplinary therapeutic effort that AL amyloidosis currently represents.In terms of the clinical characteristics, the majority of the patients began with asthenia and/or edema, due to involvement of the heart or kidneys or both organs (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), in proportions similar to that described in other series.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> In many cases, the patients had been diagnosed with cardiomyopathy of unknown origin, refractory heart failure (in cases of nephrotic syndrome) or polyradiculopathy. In terms of the diagnosis, the decision to perform biopsies was made according to clinical criteria searching for confirmation of the diagnosis and the demonstration of amyloid in organs, which could determine the prognosis and/or treatment. The biopsy of affected organs, such as the heart, kidneys or liver, showed amyloid deposits in 100% of the cases (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 3</a>). The biopsy of subcutaneous fat, rectal mucosa and saliva glands is simple. In our experience, however, the procedure has a sensitivity that varies greatly depending on the size of the sample, and a negative result does not exclude involvement of other organs. Considering that a correct histological diagnosis is essential for starting treatment, we consider it preferable to consider performing organ biopsies with clinical involvement data than to delay the diagnosis by performing biopsies of subcutaneous fat and saliva glands. We also need to consider the center's experience, both in performing biopsies and in the histological examination of biopsies,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> and the therapeutic options for the patient, given that the demonstration of amyloid deposits can change the management of the disease. There are organ disorders that can contraindicate aggressive procedures, as occurred for us with a young patient who was an HTx candidate but who had a lung disorder that resulted in this procedure being ruled out.With respect to the laboratory findings, our series confirms the fact reflected in recent publications that all the patients have a monoclonal component in serum and/or urine or changes in serum FLC levels.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The demonstration of an abnormal FLC ratio allows us to suspect the diagnosis in cases without a monoclonal component,<a class="elsevierStyleCrossRefs" href="#bib0030">6–8,14</a> and a significant difference between affected and unaffected chains can provide prognostic value.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> The amount of the reduction in affected chain defines the response to treatment.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Therefore, measuring serum FLCs is an essential technique both for the diagnosis and monitoring of patients with AL amyloidosis.The systematic implementation of BM biopsies with IHC enabled us to demonstrate an underlying LPS in 31 cases, at the expense of plasma cells in 29 of the cases. The discussion of whether a patient should be diagnosed with multiple myeloma (MM) with AL amyloidosis or with AL amyloidosis based on the number of plasma cells in the BM is academic. The World Health Organization's most recent criteria for the diagnosis of symptomatic MM<a class="elsevierStyleCrossRef" href="#bib0015">3</a> do not require a specific quantity of monoclonal protein in serum/urine or of plasma cells in BM (which vary according to the technique used) but rather the demonstration of monoclonality of the same and organ damage, with AL amyloidosis by itself a treatment criterion. However, the presence of AL amyloidosis in a patient with symptomatic MM worsens the prognosis and determines a different management approach.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>AL amyloidosis is 20 times more common than the other types of amyloidosis, but the diagnosis must be ensured before starting treatment.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> ATTR amyloidosis (due to transthyretin deposition) is the second most common type and should be suspected in patients with normal FLC levels, BM with no evidence of LPS/MM, cardiac echocardiogram or MRI indicative of amyloidosis and scintigraphy with 99 mTc-DPD with biventricular uptake in the cardiac area.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,11,13</a> IHC techniques should be performed on tissues, although occasionally the amyloid does not stain because it is a degraded protein. The presence of amyloid material in BM occurs only in AL amyloidosis, but the sensitivity is modest (50% in our series and in the literature). In questionable cases, it might be necessary to resort to techniques that are not available in most centers, such as IHC with electronic microscopy.<a class="elsevierStyleCrossRefs" href="#bib0005">1,5,15</a>The therapeutic decisions in our series were made after stratification according to ECOG score, age and affected organs, as recommended by the current guidelines<a class="elsevierStyleCrossRefs" href="#bib0005">1,5,10</a> and using the same drugs used for MM without amyloidosis: steroids, alkylating agents at standard dosage or at high dosage pre-ABMT and bortezomib. We do not recommend the use of immunomodulatory drugs (IMiDs) (thalidomide or lenalidomide) in any case due to the toxicity of these drugs. IMiDs achieve lower response rates than bortezomib,<a class="elsevierStyleCrossRef" href="#bib0090">17</a> although their use could be considered for cases that do not respond to bortezomib or for which this drug is contraindicated. There are still no conclusive results concerning the new IMiDs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib).<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Patients with LPS and no underlying MM should undergo specific regimens that usually include rituximab and alkylating agents.<a class="elsevierStyleCrossRef" href="#bib0095">18</a> Our experience is limited to 2 patients, 1 of whom showed no organ response despite a hematologic response; the other has just started treatment.We have used ABMT in patients <65 years of age and without significant cardiac impairment and in a patient following HTx. The debate as to whether a patient with AL amyloidosis should undergo ABMT or not should be considered in reverse: Is the patient in good condition for undergoing ABMT? ABMT in AL amyloidosis helps achieve complete hematological responses and prolonged survival in more than 70–80% of the patients,<a class="elsevierStyleCrossRefs" href="#bib0050">10,19</a> rates that are higher than those achieved with the new drugs. However, the response rate achieved by high doses of melphalan used in ABMT, both in AL amyloidosis and MM, is proportional to the dose of this drug. Frail patients might not tolerate these doses. The use of validated comorbidity indices that can calculate the procedure-related mortality<a class="elsevierStyleCrossRef" href="#bib0105">20</a> and the implementation of recently published recommendations<a class="elsevierStyleCrossRefs" href="#bib0025">5,10</a> can help the decision in specific cases. For cases in which we do not consider the patient to be in good condition for undergoing ABMT, we start antineoplastic treatment with combinations of bortezomib or, for frail elderly patients, alkylating agents and steroids. Taking into account our results and those published<a class="elsevierStyleCrossRefs" href="#bib0045">9,15,21</a> on bortezomib, it is worth questioning the usefulness of alkylating agents at conventional doses in AL amyloidosis other than for palliative reasons, until the results of currently ongoing randomized studies have been published.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>We cannot compare the different therapeutic approaches because, as with other series,<a class="elsevierStyleCrossRefs" href="#bib0020">4,15</a> the patients are heterogeneous and cardiac involvement determines a highly adverse prognosis in the short-term, unless the patient undergoes HTx, a procedure (along with ABMT) that is only used in selected patients. However, the use of bortezomib in combination has helped us achieve hematological and organ responses, undoubtedly improving the prognosis of patients with cardiac involvement or serious nephrotic syndrome.Cardiac involvement due to AL amyloidosis is a controversial indication for HTx, although our center and others have achieved acceptable results in selected patients.<a class="elsevierStyleCrossRef" href="#bib0115">22</a> The prognosis of a patient with NT-proBNP >8500ng/L at diagnosis is poor,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and although we have observed rapid cardiac response after treatment with bortezomib, there are patients who do not have the time for this procedure and for whom this procedure should be considered early on. Of the 5 HTx in our series, 1 patient underwent HTx without prior antineoplastic treatment; the 4 remaining patients were treated with combinations of bortezomib while their condition was evaluated. To include a patient in an HTx waiting list, it is not essential that they undergo prior antineoplastic treatment; however, taking into account the scarcity of organs and the responses that are achieved with combinations of bortezomib, it is worth starting antineoplastic treatment while waiting for an organ or for improvement. The cases we reported on of young patients who did not undergo HTx despite being indicated for the procedure and who improved after treatment with this drug are a good example. Another argument in favor of having patients who are candidates for HTx (or who have already undergone the procedure) undergo antineoplastic treatment is to prevent amyloid redeposition, a condition that we have not observed in any of the cases. There are 2 other facts that should also be considered when deciding to include a patient in an HTx waiting list. First, there are young patients with serious cardiac involvement who die early and who could have benefited from the procedure (4 in our series). Second, a patient subjected to HTx requires lifelong immunosuppression, without which they can experience fatal complications such as acute rejection (2 patients in our series).AL amyloidosis requires a correct early diagnosis, with the help of FLC measurements and the biopsies of BM and organs with clinical involvement. Cardiac involvement is the main prognostic determinant. A comprehensive cardiac evaluation that includes imaging techniques and serial reading of biomarkers such as the NT-proBNP is therefore essential.<a class="elsevierStyleCrossRefs" href="#bib0020">4,23</a> In our experience, the management of patients requires the collaboration of numerous specialists because the antineoplastic treatment and the use of procedures such as ABMT and HTx can benefit selected patients after proper stratification.<a class="elsevierStyleCrossRefs" href="#bib0020">4,5,10,19,21–23</a>Conflicts of interestI. Krsnik has collaborated on scientific advisory meetings for Celgene and Mundipharma." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres632903" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec645546" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres632904" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec645547" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0020" "titulo" => "Patients and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Additional studies" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Assessment of therapeutic response" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Clinical involvement and additional examinations" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Treatment and response" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Outcome" ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "xack213258" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-04-02" "fechaAceptado" => "2014-08-26" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec645546" "palabras" => array:6 [ 0 => "Amyloidosis" 1 => "Free light chains" 2 => "N-terminal prohormone of brain natriuretic peptide" 3 => "Bortezomib" 4 => "Autologous progenitor transplantation" 5 => "Heart transplantation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec645547" "palabras" => array:6 [ 0 => "Amiloidosis" 1 => "Cadenas ligeras libres" 2 => "Fragmento aminoterminal del péptido natriurético cerebral" 3 => "Bortezomib" 4 => "Trasplante autólogo de progenitores" 5 => "Trasplante cardiaco" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectivesAL amyloidosis is a rare condition whose management is undergoing changes due to recent advances in diagnosis and treatment. We describe a contemporary series of patients with AL amyloidosis to analyze the features that enable early diagnosis and optimal management. Patients and methodsWe recruited for analysis 32 patients (19 women; mean age, 63 years) treated consecutively at our center. ResultsEighty-four percent of the patients presented with asthenia, dyspnea or edema, with a previous duration of symptoms of 8 months (median). Cardiac (21/32) and renal impairment were the most common type (11/32). All of the patients, except one, had a monoclonal component in serum/urine or abnormal values for free light chains (78%, λ). The bone marrow (BM) showed clonal plasmacytosis in 29 cases. All of the cardiac biopsies and 50% of the BM biopsies showed amyloid deposits. The results of the echocardiogram and/or cardiac resonance were abnormal in 27/30 cases. The median NT-proBNP value at diagnosis was 5200ng/ml. Thirteen patients died due to heart failure, 2 due to rejection after heart transplantation, 2 due to pneumonia and 1 after a stroke. Ten patients did not undergo treatment, 12 were treated with bortezomib and 5 were treated with alkylating agents. Five patients underwent heart transplantation and 4 underwent autologous bone marrow transplantation. Fourteen patients achieved a complete hematologic response and 10 achieved organ response. The median survival was 17 months. ConclusionsCardiac involvement is the major determinant of prognosis. Yield of involved organ biopsy is high (100% heart biopsies). Antineoplastic treatment with bortezomib and/or autologous bone marrow transplantation achieves hematological responses with improvements in organ impairment." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Patients and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivoLa amiloidosis AL es una entidad rara cuyo manejo está cambiando gracias a avances recientes en el diagnóstico y tratamiento. Describimos una serie contemporánea de enfermos con amiloidosis AL, para analizar aspectos que permiten un diagnóstico precoz y un manejo óptimo. Pacientes y métodosHemos reunido para su análisis 32 pacientes (19 mujeres, edad mediana 63 años) atendidos consecutivamente en nuestro centro. ResultadosEl 84% de los enfermos comenzaron con astenia, disnea o edemas con una duración previa de los síntomas de 8 meses (mediana). La afectación cardiaca (21/32) y la renal fueron las más frecuentes (11/32). Todos los enfermos, excepto uno, presentaban componente monoclonal en suero/orina o valores anormales de cadenas ligeras libres (78%, λ). La médula ósea (MO) mostraba plasmocitosis clonal en 29 casos. El 100% de las biopsias cardiacas y el 50% de las de MO mostraron amiloide. El ecocardiograma y/o la resonancia cardiaca fueron anormales en 27/30 casos. La mediana de NT-proBNP al diagnóstico fue de 5200ng/mL. Trece enfermos fallecieron por insuficiencia cardiaca, 2 por rechazo tras trasplante cardiaco, 2 por neumonía y uno tras ictus. Diez enfermos no recibieron tratamiento; 12 recibieron bortezomib y 5 alquilantes. Cinco enfermos recibieron un trasplante cardiaco y 4, un autotrasplante de MO. Catorce enfermos alcanzaron respuesta hematológica completa y 10, respuesta de órganos. La supervivencia mediana fue de 17 meses. ConclusionesLa afectación cardiaca es el principal determinante pronóstico. La rentabilidad de las biopsias de órganos afectados es alta (100% biopsias cardiacas). El tratamiento antineoplásico con bortezomib y/o autotrasplante de MO consigue respuestas hematológicas con mejoría de la afectación de órganos." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Pacientes y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Krsnik I, Cabero M, Morillo D, Segovia J, García-Pavía P, Gómez-Bueno M, et al. Amiloidosis de cadenas ligeras: experiencia en un hospital terciario 2005–2013. Rev Clin Esp. 2015;215:1–8." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1070 "Ancho" => 1202 "Tamanyo" => 89240 ] ] "descripcion" => array:1 [ "en" => "Serum immunochemistry results. FLC: free light chains." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviation: ECOG, Eastern Cooperative Oncology Group.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>" "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sex (♀; ♂) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19; 13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Age, years</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39–87 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038045.png" ] ] 1 => 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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">n (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Complaint</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bone pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Syncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lump \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Neuropathic pain \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Edema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Constitutional syndrome/asthenia/dyspnea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">19 (60) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Symptoms, median (range), months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (3–48) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Referring department</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cardiology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">20 (62) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Nephrology \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (25) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Internal medicine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (12) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">ECOG score at diagnosis</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">≤1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (15) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 (31) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">≥3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 (53) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Number of affected organs</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (28) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 (47) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">≥3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 (25) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038044.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Demographic and clinical data at the time of diagnosis. symptoms: duration of symptoms before diagnosis." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Abbreviations: AP, alkaline phosphatase; Echo, echocardiogram; eGFR, estimated glomerular filtration rate; HF, heart failure; MRI, cardiac magnetic resonance imaging; NT-proBNP, amino-terminal fragment of the brain natriuretic peptide." "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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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">N \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Cardiovascular system</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HF signs/symptoms \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Pacemakers \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Abnormal echo and/or MRI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27/30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NT-proBNP at diagnosis: median \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.200 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">131–84,000 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">>332ng/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27/31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">>8.500ng/L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12/31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Kidney</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">eGFR <40mL/min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hemodialysis \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Nephrotic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Digestive system</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hepatomegaly/↑ AP \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Gastrointestinal bleeding \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Macroglossia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Peripheral nervous system</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Polyneuropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Carpal tunnel syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Autonomic nervous system</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Orthostatic hypotension/syncope \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Diarrhea \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></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Others</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lytic bone lesions \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hypercalcemia \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Skin lesions \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></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Factor×defect \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></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038047.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Organ involvement over the course of the evolution." ] ] 3 => array:7 [ "identificador" => "tbl0025" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "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">Tissue \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">Biopsies/amyloid \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Bone marrow \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">32/16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Heart \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18/18 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Kidney \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Colon/rectum \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Saliva glands \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11/4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Subcutaneous fat \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5/3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Liver \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2/2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Tongue \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lung \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sural nerve \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lymph node \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1/1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038046.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Biopsies performed/biopsies with amyloid deposits." ] ] 4 => array:7 [ "identificador" => "tbl0035" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "The + sign indicates survival of patients who are still alive.Abbreviations: ABMT, autologous bone marrow transplantation; C, combinations; CR, complete response; HTx, heart transplantation; NT-proBNP, amino-terminal fragment of the brain natriuretic peptide; PNP, polyneuropathy; R-CFM, rituximab-cyclophosphamide; SD, stable disease; VEF, ventricular ejection fraction; VGPR, very good partial response." "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">Treatment \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">N (living) \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">Hematologic response \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">Organ response \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">Survival, months \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C bortezomib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 (5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No No Yes: ↓ NT-proBNP Yes: ↓ NT-proBNP Yes: ↓ NT-proBNP Yes: ↓ NT-proBNP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 +7 +13 +19 +22 46 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 VGPR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes:↓ NT-proBNP ↑ VEF and nephrotic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">+31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C bortezomib +ABMT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">+47 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C bortezomib + HTx \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4 CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not assessable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28, +58, +65, +69 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C alkylating agents \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 VGPR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (macroglossia, renal function; no response) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">35, 46; 11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 SD \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="char" valign="top">+17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 no response \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="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ABMT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 CR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotic syndrome + PNP Nephrotic syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">+51 +98 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HTx + ABMT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not assessable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not assessable \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">R-CFM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CR \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="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1038048.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Treatment administered and response achieved (hematologic and clinical)." ] ] 5 => array:5 [ "identificador" => "tb0005" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "What we know?AL amyloidosis by deposition of light chains is the most common form of amyloidosis. Although it has been described extensively in the literature, there are new techniques that enable a better determination of the heart's condition. Furthermore, the advent of new therapies such as proteasome inhibitors and the development of transplants have changed the natural evolution of this disease. This study shows how these factors have affected a series of patients in our community.What this article provides?AL amyloidosis is still a disease with a poor prognosis, with a mean survival of 17 months after the diagnosis, and cardiac involvement is its main determinant. The combination of imaging tests enables us to suspect cardiac involvement, and the biopsy of affected organs offers a high diagnostic yield. The use of bone marrow and heart transplantation in selected patients can produce a significant benefit.The Editors" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How I treat: amyloidosis; the importante of accurate diagnosis and amyloid typing" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N. Leung" 1 => "S.H. Nasr" 2 => "S. Sethi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2012-03-413682" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2012" "volumen" => "120" "paginaInicial" => "3206" "paginaFinal" => "3213" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22948045" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.D. Sipe" 1 => "M.D. Benson" 2 => "J.N. Buxbaum" 3 => "S. Ikeda" 4 => "G. Merlini" 5 => "M.J. 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"vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/22548874/0000021500000001/v2_201605010053/S2254887414001350/v2_201605010053/en/main.assets" "Apartado" => array:4 [ "identificador" => "1901" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original Articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/22548874/0000021500000001/v2_201605010053/S2254887414001350/v2_201605010053/en/main.pdf?idApp=WRCEE&text.app=https://revclinesp.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2254887414001350?idApp=WRCEE"]

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Light chain amyloidosis: Experience in a tertiary hospital: 2005–2013

Amiloidosis de cadenas ligeras: experiencia en un hospital terciario 2005–2013

I. Krsnika,

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isabel.krsnik@salud.madrid.org

Corresponding author.

, M. Caberoa, D. Morilloa, J. Segoviab, P. García-Pavíab, M. Gómez-Buenob, C. Salasc

a Servicio de Hematología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain

b Servicio de Cardiología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain

c Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain

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light chains of degraded monoclonal immunoglobulins are deposited&#44; which are always produced by a neoplasm of lymphoproliferative origin&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Patients usually report highly nonspecific symptoms&#44; which delays the diagnosis&#46; More than a third of patients start with serious impairment of various organs&#46; In recent years&#44; there have been significant developments in the diagnosis and treatment of patients with AL amyloidosis&#46; These advances include the measurement of the amino-terminal fragment of the brain natriuretic peptide &#40;NT-proBNP&#41; and the use of magnetic resonance imaging &#40;MRI&#41; to assess cardiac impairment&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> The quantification of serum free light chains &#40;FLCs&#41; of immunoglobulins can provide the basis for suspecting the presence of an underlying neoplasm of lymphoproliferative origin&#44; which can advance the diagnosis and help monitor the treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> From the therapeutic point of view&#44; another advance is the emergence of bortezomib&#44; a proteasome inhibitor that improves organ impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Risk stratification of patients<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;10</span></a> helps when making therapeutic decisions and when using the most rational modalities such as autologous bone marrow transplantation &#40;ABMT&#41; and heart transplantation &#40;HTx&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The aim of this study is to describe a contemporary series of patients with AL amyloidosis to analyze the issues that could contribute to an earlier diagnosis and optimal management&#44; with special mention of the therapeutic options available in our community&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patients and methods</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Patients</span><p id="par0035" class="elsevierStylePara elsevierViewall">Our series included 32 consecutive patients treated at the Department of Hematology of the University Hospital Puerta de Hierro&#44; Majadahonda &#40;Madrid&#44; Spain&#41; between 2005 and 2013 who had an unequivocal histological diagnosis of AL amyloidosis&#46; To this end&#44; we required deposits of amyloid material that stained positive for Congo red in tissue and the demonstration of monoclonality using immunoglobulin light chain antibodies &#40;immunohistochemistry &#91;IHC&#93;&#41;&#46; In cases in which the IHC of the amyloid tissue did not show monoclonality&#44; we required the presence of amyloids in the bone marrow &#40;BM&#41; or cardiac biopsy&#44; after specifically ruling out the deposit of other proteins such as transthyretin &#40;TTR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The patients were studied and treated according to the healthcare protocols of the Departments of Hematology and Cardiology&#44; and the patients gave their informed consent to participate in the study&#46; The data collection and the preparation of this article were approved by the Ethics Committee of the University Hospital Puerta de Hierro and comply with the specifications of the Declaration of Helsinki&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Additional studies</span><p id="par0045" class="elsevierStylePara elsevierViewall">Clinical&#44; laboratory and BM biopsy data were collected prospectively by the Department of Hematology&#46; The results of the cardiac imaging tests and endomyocardial biopsies were analyzed retrospectively&#46; The clinical data included demographic data&#44; general condition &#40;Eastern Cooperative Oncology Group &#91;ECOG&#93; scale&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> clinical involvement of organs and systems&#44; treatment received and treatment response&#44; survival as of January 1&#44; 2014&#44; 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2014&#44; the date when the data collection was closed&#46; <a class="elsevierStyleCrossRef" href="#tbl0025">Table 3</a> shows the results of the biopsies&#46; In terms of the immunochemistry studies&#44; 19 cases showed a monoclonal component in serum and 8 showed abnormal FLC values with no monoclonal component&#46; In 5 cases that showed no monoclonal component&#44; the FLCs were not measured &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Twenty-four of the 32 cases showed a monoclonal component in urine&#46; Overall&#44; 31&#47;32 cases showed abnormal immunochemical data&#44; either in serum or in urine&#46; FLCs could not be measured in 1 case with negative IF in serum and urine &#40;the technique was not available at the time&#41;&#44; and the diagnosis was conducted by IHC analysis of the amyloid&#46; The clonality of the light chain demonstrated in BM&#47;serum&#47;urine or the IHC analysis of the amyloid was &#955; in 25 cases and &#954; in 7 cases&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The BM studies showed a population of plasma cells with clonality equal to that of the serum&#47;urine in 29 cases &#40;90&#37;&#41;&#59; 10 cases with infiltration &#60;10&#37; and 19 with infiltration &#8805;10&#37;&#46; One case showed no excess of monoclonal plasma cells in the BM&#59; however&#44; an excess was evident in the skin in the form of a plasmacytoma accompanied by amyloid material&#46; Two cases showed infiltration of the BM by a low-grade CD20-positive B-cell lymphoproliferative syndrome &#40;LPS&#41;&#46; None of the 25 scintigraphy studies performed with <span class="elsevierStyleSup">99m</span>TC-DPD showed biventricular uptake in the cardiac area &#40;visual score 0&#8211;1&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Treatment and response</span><p id="par0090" class="elsevierStylePara elsevierViewall">Ten patients did not undergo treatment&#59; 8 due to early <span class="elsevierStyleItalic">exitus</span> &#40;median survival after diagnosis&#44; 30 days&#41;&#44; 1 due to absence of indication &#40;AL amyloidosis with cutaneous plasmacytoma&#41; and 1 for previous disabling stroke&#46; Another recently diagnosed case was excluded from the analysis because the patient had just started treatment&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a> shows the treatments undergone and the hematologic and organ response of the 21 treated patients&#46; Twelve of these patients were treated with combinations of bortezomib &#40;with alkylating agents&#44; steroids or both&#41;&#44; 5 patients were treated with alkylating agents plus steroids&#44; and 1 was treated with rituximab and cyclophosphamide &#40;CD20&#43; SLP&#41;&#46; One patient underwent an HTx immediately after the diagnosis with no previous treatment and then subsequently underwent an ABMT&#46; Two patients underwent ABMT without prior treatment&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Fourteen patients were treated with high doses of bortezomib and&#47;or melphalan as conditioning for ABMT&#44; and of these&#44; 12 achieved complete hematologic response&#46; Of the 10 patients treated with bortezomib and&#47;or ABMT and without HTx&#44; 8 achieved organ response &#40;1 died early and 1 has just completed treatment&#41;&#46; Five patients treated with bortezomib combinations achieved cardiac response&#46; Of these&#44; 3 met cardiac criteria for HTx but were not included in the waiting lists due to rejection of the technique&#44; lung impairment and age limit&#44; respectively&#46; The NT-proBNP levels began to descend in these 5 cases 4&#8211;6 months after starting the treatment&#46; A patient in this group died 46 months after diagnosis following a stroke of embolic origin&#44; having refused to undergo anticoagulant treatment&#46; In the cases with nephrotic-range proteinuria&#44; the protein levels in urine began to descend later &#40;8&#8211;12 months after starting the treatment&#41; and continued to descend for 2&#8211;3 years&#46; The response of the affected organs after medical treatment could not be assessed for those patients who underwent a HTx&#46; These 5 patients improved after the procedure&#44; with an ECOG score of 0 at 3 months of the operation&#46; All underwent antineoplastic treatment before and&#47;or after the HTx&#46; Three of these patients are still living &#40;44&#44; 47 and 60 months after the procedure&#41;&#44; with an ECOG score of 0&#8211;1&#46; We have observed no new amyloid deposits in the heart in any of the patients who underwent HTx&#44; in whom 8&#8211;16 serial endomyocardial biopsies were performed during the first year&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Of the 12 patients with NT-proBNP levels &#62;8500<span class="elsevierStyleHsp" style=""></span>ng&#47;L at diagnosis&#44; 3 who underwent a HTx and 1 who was treated with bortezomib in combination survived&#59; the remaining 8 died in less than 6 months&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The group of 14 surviving patients included 1 patient with a cutaneous plasmacytoma without indication for treatment at present&#44; 3 with primarily renal impairment &#40;nephrotic syndrome&#41; and who underwent ABMT&#44; 3 who underwent HTx and 5 with multiple organ involvement who have completed treatment&#46; With the exception of 2 patients who underwent ABMT without prior antineoplastic treatment and one who has just begun treatment&#44; the rest of the survivors were or are currently being treated with bortezomib in combination with alkylating agents and&#47;or steroids &#40;<a class="elsevierStyleCrossRef" href="#tbl0035">Table 4</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Outcome</span><p id="par0115" class="elsevierStylePara elsevierViewall">The median overall survival from diagnosis was 17 months &#40;range&#58; 1&#8211;98&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Fourteen patients &#40;43&#37;&#41; &#40;median age&#44; 59 years&#59; range&#44; 53&#8211;86 years&#41; were still alive on January 1&#44; 2014&#44; with a median survival after diagnosis of 27&#46;5 months &#40;range&#44; 5&#8211;98 months&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Eighteen &#40;56&#37;&#41; patients died&#44; 13 of them due to heart failure and 2 due to acute rejection of the heart transplant&#59; another 2 patients died from pneumonia and 1 died after a stroke&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0130" class="elsevierStylePara elsevierViewall">In this study&#44; we described the clinical characteristics&#44; diagnostic issues&#44; assessment&#44; evolution and treatment of a contemporary series of 32 patients with AL amyloidosis treated at a tertiary hospital in Spain&#46; Our series adequately illustrates the clinical variability&#44; diagnostic complexity and&#44; especially&#44; the multidisciplinary therapeutic effort that AL amyloidosis currently represents&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In terms of the clinical characteristics&#44; the majority of the patients began with asthenia and&#47;or edema&#44; due to involvement of the heart or kidneys or both organs &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; in proportions similar to that described in other series&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In many cases&#44; the patients had been diagnosed with cardiomyopathy of unknown origin&#44; refractory heart failure &#40;in cases of nephrotic syndrome&#41; or polyradiculopathy&#46; In terms of the diagnosis&#44; the decision to perform biopsies was made according to clinical criteria searching for confirmation of the diagnosis and the demonstration of amyloid in organs&#44; which could determine the prognosis and&#47;or treatment&#46; The biopsy of affected organs&#44; such as the heart&#44; kidneys or liver&#44; showed amyloid deposits in 100&#37; of the cases &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 3</a>&#41;&#46; The biopsy of subcutaneous fat&#44; rectal mucosa and saliva glands is simple&#46; In our experience&#44; however&#44; the procedure has a sensitivity that varies greatly depending on the size of the sample&#44; and a negative result does not exclude involvement of other organs&#46; Considering that a correct histological diagnosis is essential for starting treatment&#44; we consider it preferable to consider performing organ biopsies with clinical involvement data than to delay the diagnosis by performing biopsies of subcutaneous fat and saliva glands&#46; We also need to consider the center&#39;s experience&#44; both in performing biopsies and in the histological examination of biopsies&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and the therapeutic options for the patient&#44; given that the demonstration of amyloid deposits can change the management of the disease&#46; There are organ disorders that can contraindicate aggressive procedures&#44; as occurred for us with a young patient who was an HTx candidate but who had a lung disorder that resulted in this procedure being ruled out&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">With respect to the laboratory findings&#44; our series confirms the fact reflected in recent publications that all the patients have a monoclonal component in serum and&#47;or urine or changes in serum FLC levels&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The demonstration of an abnormal FLC ratio allows us to suspect the diagnosis in cases without a monoclonal component&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8&#44;14</span></a> and a significant difference between affected and unaffected chains can provide prognostic value&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The amount of the reduction in affected chain defines the response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Therefore&#44; measuring serum FLCs is an essential technique both for the diagnosis and monitoring of patients with AL amyloidosis&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The systematic implementation of BM biopsies with IHC enabled us to demonstrate an underlying LPS in 31 cases&#44; at the expense of plasma cells in 29 of the cases&#46; The discussion of whether a patient should be diagnosed with multiple myeloma &#40;MM&#41; with AL amyloidosis or with AL amyloidosis based on the number of plasma cells in the BM is academic&#46; The World Health Organization&#39;s most recent criteria for the diagnosis of symptomatic MM<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> do not require a specific quantity of monoclonal protein in serum&#47;urine or of plasma cells in BM &#40;which vary according to the technique used&#41; but rather the demonstration of monoclonality of the same and organ damage&#44; with AL amyloidosis by itself a treatment criterion&#46; However&#44; the presence of AL amyloidosis in a patient with symptomatic MM worsens the prognosis and determines a different management approach&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">AL amyloidosis is 20 times more common than the other types of amyloidosis&#44; but the diagnosis must be ensured before starting treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> ATTR amyloidosis &#40;due to transthyretin deposition&#41; is the second most common type and should be suspected in patients with normal FLC levels&#44; BM with no evidence of LPS&#47;MM&#44; cardiac echocardiogram or MRI indicative of amyloidosis and scintigraphy with 99 mTc-DPD with biventricular uptake in the cardiac area&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;11&#44;13</span></a> IHC techniques should be performed on tissues&#44; although occasionally the amyloid does not stain because it is a degraded protein&#46; The presence of amyloid material in BM occurs only in AL amyloidosis&#44; but the sensitivity is modest &#40;50&#37; in our series and in the literature&#41;&#46; In questionable cases&#44; it might be necessary to resort to techniques that are not available in most centers&#44; such as IHC with electronic microscopy&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5&#44;15</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The therapeutic decisions in our series were made after stratification according to ECOG score&#44; age and affected organs&#44; as recommended by the current guidelines<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5&#44;10</span></a> and using the same drugs used for MM without amyloidosis&#58; steroids&#44; alkylating agents at standard dosage or at high dosage pre-ABMT and bortezomib&#46; We do not recommend the use of immunomodulatory drugs &#40;IMiDs&#41; &#40;thalidomide or lenalidomide&#41; in any case due to the toxicity of these drugs&#46; IMiDs achieve lower response rates than bortezomib&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">17</span></a> although their use could be considered for cases that do not respond to bortezomib or for which this drug is contraindicated&#46; There are still no conclusive results concerning the new IMiDs &#40;pomalidomide&#41; and proteasome inhibitors &#40;carfilzomib&#44; ixazomib&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Patients with LPS and no underlying MM should undergo specific regimens that usually include rituximab and alkylating agents&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">18</span></a> Our experience is limited to 2 patients&#44; 1 of whom showed no organ response despite a hematologic response&#59; the other has just started treatment&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">We have used ABMT in patients &#60;65 years of age and without significant cardiac impairment and in a patient following HTx&#46; The debate as to whether a patient with AL amyloidosis should undergo ABMT or not should be considered in reverse&#58; Is the patient in good condition for undergoing ABMT&#63; ABMT in AL amyloidosis helps achieve complete hematological responses and prolonged survival in more than 70&#8211;80&#37; of the patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;19</span></a> rates that are higher than those achieved with the new drugs&#46; However&#44; the response rate achieved by high doses of melphalan used in ABMT&#44; both in AL amyloidosis and MM&#44; is proportional to the dose of this drug&#46; Frail patients might not tolerate these doses&#46; The use of validated comorbidity indices that can calculate the procedure-related mortality<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">20</span></a> and the implementation of recently published recommendations<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;10</span></a> can help the decision in specific cases&#46; For cases in which we do not consider the patient to be in good condition for undergoing ABMT&#44; we start antineoplastic treatment with combinations of bortezomib or&#44; for frail elderly patients&#44; alkylating agents and steroids&#46; Taking into account our results and those published<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;15&#44;21</span></a> on bortezomib&#44; it is worth questioning the usefulness of alkylating agents at conventional doses in AL amyloidosis other than for palliative reasons&#44; until the results of currently ongoing randomized studies have been published&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">We cannot compare the different therapeutic approaches because&#44; as with other series&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;15</span></a> the patients are heterogeneous and cardiac involvement determines a highly adverse prognosis in the short-term&#44; unless the patient undergoes HTx&#44; a procedure &#40;along with ABMT&#41; that is only used in selected patients&#46; However&#44; the use of bortezomib in combination has helped us achieve hematological and organ responses&#44; undoubtedly improving the prognosis of patients with cardiac involvement or serious nephrotic syndrome&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Cardiac involvement due to AL amyloidosis is a controversial indication for HTx&#44; although our center and others have achieved acceptable results in selected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">22</span></a> The prognosis of a patient with NT-proBNP &#62;8500<span class="elsevierStyleHsp" style=""></span>ng&#47;L at diagnosis is poor&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and although we have observed rapid cardiac response after treatment with bortezomib&#44; there are patients who do not have the time for this procedure and for whom this procedure should be considered early on&#46; Of the 5 HTx in our series&#44; 1 patient underwent HTx without prior antineoplastic treatment&#59; the 4 remaining patients were treated with combinations of bortezomib while their condition was evaluated&#46; To include a patient in an HTx waiting list&#44; it is not essential that they undergo prior antineoplastic treatment&#59; however&#44; taking into account the scarcity of organs and the responses that are achieved with combinations of bortezomib&#44; it is worth starting antineoplastic treatment while waiting for an organ or for improvement&#46; The cases we reported on of young patients who did not undergo HTx despite being indicated for the procedure and who improved after treatment with this drug are a good example&#46; Another argument in favor of having patients who are candidates for HTx &#40;or who have already undergone the procedure&#41; undergo antineoplastic treatment is to prevent amyloid redeposition&#44; a condition that we have not observed in any of the cases&#46; There are 2 other facts that should also be considered when deciding to include a patient in an HTx waiting list&#46; First&#44; there are young patients with serious cardiac involvement who die early and who could have benefited from the procedure &#40;4 in our series&#41;&#46; Second&#44; a patient subjected to HTx requires lifelong immunosuppression&#44; without which they can experience fatal complications such as acute rejection &#40;2 patients in our series&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">AL amyloidosis requires a correct early diagnosis&#44; with the help of FLC measurements and the biopsies of BM and organs with clinical involvement&#46; Cardiac involvement is the main prognostic determinant&#46; A comprehensive cardiac evaluation that includes imaging techniques and serial reading of biomarkers such as the NT-proBNP is therefore essential&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;23</span></a> In our experience&#44; the management of patients requires the collaboration of numerous specialists because the antineoplastic treatment and the use of procedures such as ABMT and HTx can benefit selected patients after proper stratification&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5&#44;10&#44;19&#44;21&#8211;23</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">I&#46; Krsnik has collaborated on scientific advisory meetings for Celgene and Mundipharma&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">AL amyloidosis is a rare condition whose management is undergoing changes due to recent advances in diagnosis and treatment&#46; We describe a contemporary series of patients with AL amyloidosis to analyze the features that enable early diagnosis and optimal management&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We recruited for analysis 32 patients &#40;19 women&#59; mean age&#44; 63 years&#41; treated consecutively at our center&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Eighty-four percent of the patients presented with asthenia&#44; dyspnea or edema&#44; with a previous duration of symptoms of 8 months &#40;median&#41;&#46; Cardiac &#40;21&#47;32&#41; and renal impairment were the most common type &#40;11&#47;32&#41;&#46; All of the patients&#44; except one&#44; had a monoclonal component in serum&#47;urine or abnormal values for free light chains &#40;78&#37;&#44; &#955;&#41;&#46; The bone marrow &#40;BM&#41; showed clonal plasmacytosis in 29 cases&#46; All of the cardiac biopsies and 50&#37; of the BM biopsies showed amyloid deposits&#46; The results of the echocardiogram and&#47;or cardiac resonance were abnormal in 27&#47;30 cases&#46; The median NT-proBNP value at diagnosis was 5200<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; Thirteen patients died due to heart failure&#44; 2 due to rejection after heart transplantation&#44; 2 due to pneumonia and 1 after a stroke&#46; Ten patients did not undergo treatment&#44; 12 were treated with bortezomib and 5 were treated with alkylating agents&#46; Five patients underwent heart transplantation and 4 underwent autologous bone marrow transplantation&#46; Fourteen patients achieved a complete hematologic response and 10 achieved organ response&#46; The median survival was 17 months&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cardiac involvement is the major determinant of prognosis&#46; Yield of involved organ biopsy is high &#40;100&#37; heart biopsies&#41;&#46; Antineoplastic treatment with bortezomib and&#47;or autologous bone marrow transplantation achieves hematological responses with improvements in organ impairment&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La amiloidosis AL es una entidad rara cuyo manejo est&#225; cambiando gracias a avances recientes en el diagn&#243;stico y tratamiento&#46; Describimos una serie contempor&#225;nea de enfermos con amiloidosis AL&#44; para analizar aspectos que permiten un diagn&#243;stico precoz y un manejo &#243;ptimo&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Hemos reunido para su an&#225;lisis 32 pacientes &#40;19 mujeres&#44; edad mediana 63 a&#241;os&#41; atendidos consecutivamente en nuestro centro&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El 84&#37; de los enfermos comenzaron con astenia&#44; disnea o edemas con una duraci&#243;n previa de los s&#237;ntomas de 8 meses &#40;mediana&#41;&#46; La afectaci&#243;n cardiaca &#40;21&#47;32&#41; y la renal fueron las m&#225;s frecuentes &#40;11&#47;32&#41;&#46; Todos los enfermos&#44; excepto uno&#44; presentaban componente monoclonal en suero&#47;orina o valores anormales de cadenas ligeras libres &#40;78&#37;&#44; &#955;&#41;&#46; La m&#233;dula &#243;sea &#40;MO&#41; mostraba plasmocitosis clonal en 29 casos&#46; El 100&#37; de las biopsias cardiacas y el 50&#37; de las de MO mostraron amiloide&#46; El ecocardiograma y&#47;o la resonancia cardiaca fueron anormales en 27&#47;30 casos&#46; La mediana de NT-proBNP al diagn&#243;stico fue de 5200<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; Trece enfermos fallecieron por insuficiencia cardiaca&#44; 2 por rechazo tras trasplante cardiaco&#44; 2 por neumon&#237;a y uno tras ictus&#46; Diez enfermos no recibieron tratamiento&#59; 12 recibieron bortezomib y 5 alquilantes&#46; Cinco enfermos recibieron un trasplante cardiaco y 4&#44; un autotrasplante de MO&#46; Catorce enfermos alcanzaron respuesta hematol&#243;gica completa y 10&#44; respuesta de &#243;rganos&#46; La supervivencia mediana fue de 17 meses&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La afectaci&#243;n cardiaca es el principal determinante pron&#243;stico&#46; La rentabilidad de las biopsias de &#243;rganos afectados es alta &#40;100&#37; biopsias cardiacas&#41;&#46; El tratamiento antineopl&#225;sico con bortezomib y&#47;o autotrasplante de MO consigue respuestas hematol&#243;gicas con mejor&#237;a de la afectaci&#243;n de &#243;rganos&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Antecedentes y objetivo"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Pacientes y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Krsnik I&#44; Cabero M&#44; Morillo D&#44; Segovia J&#44; Garc&#237;a-Pav&#237;a P&#44; G&#243;mez-Bueno M&#44; et al&#46; Amiloidosis de cadenas ligeras&#58; experiencia en un hospital terciario 2005&#8211;2013&#46; Rev Clin Esp&#46; 2015&#59;215&#58;1&#8211;8&#46;</p>"
      ]
    ]
    "multimedia" => array:6 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1070
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            "Tamanyo" => 89240
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Serum immunochemistry results&#46; FLC&#58; free light chains&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Abbreviation&#58; ECOG&#44; Eastern Cooperative Oncology Group&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Sex</span> &#40;<span class="elsevierStyleItalic">&#9792;&#59; &#9794;</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19&#59; 13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; years</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Median&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Range&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39&#8211;87&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
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                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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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"><span class="elsevierStyleItalic">n</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Complaint</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bone pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Syncope&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lump&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neuropathic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Edema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Constitutional syndrome&#47;asthenia&#47;dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">19 &#40;60&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Symptoms&#44; median &#40;range&#41;&#44; months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;3&#8211;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Referring department</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cardiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">20 &#40;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nephrology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Internal medicine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">ECOG score at diagnosis</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8804;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8805;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Number of affected organs</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">15 &#40;47&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8805;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8 &#40;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical data at the time of diagnosis&#46; symptoms&#58; duration of symptoms before diagnosis&#46;</p>"
        ]
      ]
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AP&#44; alkaline phosphatase&#59; Echo&#44; echocardiogram&#59; eGFR&#44; estimated glomerular filtration rate&#59; HF&#44; heart failure&#59; MRI&#44; cardiac magnetic resonance imaging&#59; NT-proBNP&#44; amino-terminal fragment of the brain natriuretic peptide&#46;</p>"
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              "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="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\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"><span class="elsevierStyleItalic">N</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Cardiovascular system</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HF signs&#47;symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pacemakers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Abnormal echo and&#47;or MRI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#47;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">NT-proBNP at diagnosis&#58; median</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Range</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">131&#8211;84&#44;000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;332<span class="elsevierStyleHsp" style=""></span>ng&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27&#47;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;8&#46;500<span class="elsevierStyleHsp" style=""></span>ng&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#47;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Kidney</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>eGFR &#60;40<span class="elsevierStyleHsp" style=""></span>mL&#47;min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hemodialysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nephrotic syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Digestive system</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hepatomegaly&#47;&#8593; AP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Gastrointestinal bleeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Macroglossia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Peripheral nervous system</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Polyneuropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Carpal tunnel syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Autonomic nervous system</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Orthostatic hypotension&#47;syncope&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Others</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lytic bone lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypercalcemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Skin lesions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Factor<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>defect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1038047.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Organ involvement over the course of the evolution&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "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">Tissue&nbsp;\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">Biopsies&#47;amyloid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Bone marrow&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#47;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Heart&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#47;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kidney&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Colon&#47;rectum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Saliva glands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#47;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Subcutaneous fat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Tongue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lung&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Sural nerve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lymph node&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab1038046.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Biopsies performed&#47;biopsies with amyloid deposits&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0035"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">The &#43; sign indicates survival of patients who are still alive&#46;</p><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ABMT&#44; autologous bone marrow transplantation&#59; C&#44; combinations&#59; CR&#44; complete response&#59; HTx&#44; heart transplantation&#59; NT-proBNP&#44; amino-terminal fragment of the brain natriuretic peptide&#59; PNP&#44; polyneuropathy&#59; R-CFM&#44; rituximab-cyclophosphamide&#59; SD&#44; stable disease&#59; VEF&#44; ventricular ejection fraction&#59; VGPR&#44; very good partial response&#46;</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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\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">N &#40;living&#41;&nbsp;\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">Hematologic response&nbsp;\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">Organ response&nbsp;\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">Survival&#44;<br>months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">C bortezomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No<br>No<br>Yes&#58; &#8595; NT-proBNP<br>Yes&#58; &#8595; NT-proBNP<br>Yes&#58; &#8595; NT-proBNP<br>Yes&#58; &#8595; NT-proBNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4<br>&#43;7<br>&#43;13<br>&#43;19<br>&#43;22<br>46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 VGPR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes&#58;&#8595; NT-proBNP<br>&#8593; VEF and nephrotic syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#43;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">C bortezomib &#43;ABMT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotic syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#43;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">C bortezomib &#43; HTx&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4 &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not assessable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#44; &#43;58&#44; &#43;65&#44; &#43;69&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">C alkylating agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 VGPR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;macroglossia&#44; renal function&#59; no response&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">35&#44; 46&#59; 11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#43;17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 no response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">ABMT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2 &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotic syndrome &#43; PNP<br>Nephrotic syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#43;51<br>&#43;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">HTx &#43; ABMT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not assessable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not assessable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">R-CFM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab1038048.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Treatment administered and response achieved &#40;hematologic and clinical&#41;&#46;</p>"
        ]
      ]
      5 => array:5 [
        "identificador" => "tb0005"
        "tipo" => "MULTIMEDIATEXTO"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "texto" => array:1 [
          "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">What we know&#63;</span><p id="par0005" class="elsevierStylePara elsevierViewall">AL amyloidosis by deposition of light chains is the most common form of amyloidosis&#46; Although it has been described extensively in the literature&#44; there are new techniques that enable a better determination of the heart&#39;s condition&#46; Furthermore&#44; the advent of new therapies such as proteasome inhibitors and the development of transplants have changed the natural evolution of this disease&#46; This study shows how these factors have affected a series of patients in our community&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">What this article provides&#63;</span><p id="par0010" class="elsevierStylePara elsevierViewall">AL amyloidosis is still a disease with a poor prognosis&#44; with a mean survival of 17 months after the diagnosis&#44; and cardiac involvement is its main determinant&#46; The combination of imaging tests enables us to suspect cardiac involvement&#44; and the biopsy of affected organs offers a high diagnostic yield&#46; The use of bone marrow and heart transplantation in selected patients can produce a significant benefit&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The Editors</p></span></span>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:23 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "How I treat&#58; amyloidosis&#59; the importante of accurate diagnosis and amyloid typing"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46; Leung"
                            1 => "S&#46;H&#46; Nasr"
                            2 => "S&#46; Sethi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2012-03-413682"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2012"
                        "volumen" => "120"
                        "paginaInicial" => "3206"
                        "paginaFinal" => "3213"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22948045"
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        "texto" => "<p id="par0190" class="elsevierStylePara elsevierViewall">We would to thank the staff at Hospital Puerta de Hierro and the other hospital centers for their collaboration in managing the patients&#46;</p> <p id="par0195" class="elsevierStylePara elsevierViewall">Dr&#46; C&#46; Bellas provided the reports on the bone marrow biopsies&#44; Dr&#46; de Haro provided the scintigrams and Dr&#46; B&#46; Bornstein studied the mutations of the TTR gene&#46; All of the doctors are on the staff of University Hospital Puerta de Hierro&#46;</p>"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2014.08.002

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