Polyadenopathy is the most distinct characteristic of the disease. In many patients, three or more lymph nodes are affected. Since MCD is associated with a systemic inflammatory response, affected individuals typically present with fatigue, fever, chills and night sweats. Some patients claim nausea and vomiting, and chronic loss of appetite may result in weight loss. An increased vascular permeability, possibly triggered by VEGF, may provoke peripheral edema, pleural effusion or ascites. Pleural effusion is commonly associated with dyspnea and cough. Physical examination of MCD patients frequently reveals hepatosplenomegaly, and in fact, hepatic insufficiency may contribute to hypoalbuminemia and subsequent formation of edema. Jaundice may be noted. Additional complaints consistent with MCD are xerostomia, rash and neurological deficits [8]. MCD may progress to non-Hodgkin lymphoma, particularly in patients infected with HIV.

• Generalized Lymphadenopathy

  Multicentric Castleman's disease (MCD) is a rare disorder characterized by fever, polyclonal hypergammaglobulinemia, and generalized lymphadenopathy. [ncbi.nlm.nih.gov]

  MCD Symptoms - Multicentric Castleman’s Disease MCD clinical features range from waxing and waning mild lymphadenopathy with B-symptoms to more severe cases involving intense inflammation, generalized lymphadenopathy, hepatosplenomegaly, vascular leak [checkorphan.org]

  The etiology of HIV- and HHV-8-negative MCD is unknown. 2 Patients usually present with generalized lymphadenopathy, which may be accompanied by hepatosplenomegaly in severe cases. [secure.medicalletter.org]

• Mediastinal Lymphadenopathy

  He exhibited an accelerated erythrosedimentation rate, polyclonal hypergammaglobulinemia, and multiple cervical and thoracic mediastinal lymphadenopathies. [ncbi.nlm.nih.gov]

  lymphadenopathy Mediastinal lymphadenopathy (large center chest lymph nodes) Mediastinal lymphadenopathy (large lymph nodes chest ) Reactive hyperplasia of LN Reactive hyperplasia of lymph node Clinical Information A clinical finding indicating that [icd9data.com]

  Parenchymal lung involvement of the disease is exceedingly rare. [1] Angiofollicular or giant lymph node hyperplasia was first described in 1954 by Benjamin Castleman as a cause of mediastinal lymphadenopathy. [2] The disease has been classified on clinical [lungindia.com]

  lymphadenopathy in five cases. [erj.ersjournals.com]

• Abdominal Lymphadenopathy

  Computerized axial tomography (CT) scans showed splenomegaly and intra-abdominal lymphadenopathy, confirmed by positron emission tomography. Cervical lymph node biopsies were consistent with MCD. [ncbi.nlm.nih.gov]

  For multicentric disease: multi-region CT bilateral hilar and mediastinal lymphadenopathy centrilobular nodules diffuse abdominal lymphadenopathy hepatosplenomegaly ascites MRI General signal characteristics include: T1: iso to hyperintense relative to [radiopaedia.org]

• Fever

  Case 1: A 57-year-old woman had fever, anemia, anasarca, and some small cervical lymphadenopathy. [ncbi.nlm.nih.gov]

• Lymphadenopathy

  In this study, we examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy. [ncbi.nlm.nih.gov]

• Anemia

  Case 1: A 57-year-old woman had fever, anemia, anasarca, and some small cervical lymphadenopathy. [ncbi.nlm.nih.gov]

• Fatigue

  Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD-SS and FACIT-Fatigue scale. [ncbi.nlm.nih.gov]

  Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD–SS and FACIT–Fatigue scale. [dash.harvard.edu]

• Weight Loss

  A 49-year-old man with superficial lymphadenopathy presented with symptoms of low-grade fever, general fatigue and weight loss. On examination, multiple superficial lymphadenopathies and brown macules were observed on the trunk. [ncbi.nlm.nih.gov]

  Other symptoms include unexplained weight loss, fever, fatigue, or a sense of fullness in the chest or abdomen. [disabilitybenefitscenter.org]

  Symptoms and laboratory tests associated with MCD are general but can include the following: fever unexpected tiredness unexpected weight loss night sweats nausea vomiting loss of appetite rash swollen legs less-than-normal levels of red blood cells If [catie.ca]

• Cough

  This is a 64-year-old woman, she had repeated cough, fever and breathlessness for more than 1 year. CT imaging showed multiple small nodules in both the lungs at the first onset. Large nodes and masses in both the lungs evolved 1 year later. [ncbi.nlm.nih.gov]

  […] unexpected tiredness unexpected weight loss night sweats nausea vomiting loss of appetite rash swollen legs less-than-normal levels of red blood cells If lymph nodes are enlarged in the chest, affected people may have difficulty breathing and may also cough [catie.ca]

  Additionally, MCD patients may suffer from peripheral edema, breathing difficulties and cough as well as jaundice. These symptoms result from an excess inflammatory response. [symptoma.com]

  Symptoms and signs of MCD include fever, night sweats, loss of appetite, nausea/vomiting, weight loss, cough, shortness of breath, weakness or fatigue from anemia, enlarged lymph nodes (around the neck, collarbone, underarm, and groin area), enlarged [secure.ssa.gov]

• Pleural Effusion

  Here, we report two cases of MCD associated with marked pleural effusion, ascites, and thrombocytopenia, and discuss the independence of the TAFRO syndrome (Castleman-Kojima disease). [ncbi.nlm.nih.gov]

• Dyspnea

  He was treated with plasmapheresis, resulting in a transient improvement of dyspnea. Then, he was given humanized anti-interleukin-6 receptor antibody (tocilizumab), which resulted in the dramatic improvement of dyspnea and PH a few weeks later. [ncbi.nlm.nih.gov]

  (adequate pulmonary function is defined as pulse oximetry 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest, history of interstitial pneumonitis, etc.)); Fasting cholesterol 300 mg/dL or fasting triglyceride 400 [clinicaltrials.gov]

  Pleural effusion is commonly associated with dyspnea and cough. Physical examination of MCD patients frequently reveals hepatosplenomegaly, and in fact, hepatic insufficiency may contribute to hypoalbuminemia and subsequent formation of edema. [symptoma.com]

• Nausea

  We report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. [ncbi.nlm.nih.gov]

  Symptoms and laboratory tests associated with MCD are general but can include the following: fever unexpected tiredness unexpected weight loss night sweats nausea vomiting loss of appetite rash swollen legs less-than-normal levels of red blood cells If [catie.ca]

  The signs and symptoms of MCD are often nonspecific, and are mild in some people but life-threatening in others.[1][2] Symptoms may include enlarged lymph nodes in multiple regions, fever, weight loss, nausea, rash, and/or an enlarged large liver and [rarediseases.info.nih.gov]

  Symptoms and signs of MCD include fever, night sweats, loss of appetite, nausea/vomiting, weight loss, cough, shortness of breath, weakness or fatigue from anemia, enlarged lymph nodes (around the neck, collarbone, underarm, and groin area), enlarged [secure.ssa.gov]

• Vomiting

  We report the case of a patient presenting with postprandial vomiting of 1 month duration consistent with partial small bowel obstruction secondary to terminal ileum intussusception. [ncbi.nlm.nih.gov]

  Symptoms and laboratory tests associated with MCD are general but can include the following: fever unexpected tiredness unexpected weight loss night sweats nausea vomiting loss of appetite rash swollen legs less-than-normal levels of red blood cells If [catie.ca]

  Symptoms and signs of MCD include fever, night sweats, loss of appetite, nausea/vomiting, weight loss, cough, shortness of breath, weakness or fatigue from anemia, enlarged lymph nodes (around the neck, collarbone, underarm, and groin area), enlarged [secure.ssa.gov]

• Loss of Appetite

  Symptoms and laboratory tests associated with MCD are general but can include the following: fever unexpected tiredness unexpected weight loss night sweats nausea vomiting loss of appetite rash swollen legs less-than-normal levels of red blood cells If [catie.ca]

  The most common 'B Symptoms' of MCD are high fevers, night sweats, weight loss, and loss of appetite. Acute episodes can display significant clinical overlap with acute viral illnesses, autoimmune diseases, hematologic malignancies, and even sepsis. [checkorphan.org]

  Symptoms and signs of MCD include fever, night sweats, loss of appetite, nausea/vomiting, weight loss, cough, shortness of breath, weakness or fatigue from anemia, enlarged lymph nodes (around the neck, collarbone, underarm, and groin area), enlarged [secure.ssa.gov]

• Abdominal Pain

  A 49-year-old man with HIV infection presented with 1-week duration of low-grade fever, night sweats, left sided abdominal pain, and generalized weakness. [ncbi.nlm.nih.gov]

  Case: Abdominal tomography of a 16-year-old girl with abdominal pain and anemia; A mass of 6 * 5 cm was detected in the liver inferior. Surgical excision was done. Pathology Findings; hyaline vasculature and plasma cell components. [bildirim.org]

  In April 2018, he presented to his local hospital with fatigue, fever, dyspnea, and thoracic and abdominal pain. Clinical examination revealed generalized lymphadenopathy, hepatosplenomegaly, and edema. [nn.neurology.org]

  Case Presentation : A 25-year-old man of West African origin with HIV complained of asthenia, weight loss, fever, and abdominal pain. [pubfacts.com]

• Xerostomia

  Additional complaints consistent with MCD are xerostomia, rash and neurological deficits. MCD may progress to non-Hodgkin lymphoma, particularly in patients infected with HIV. [symptoma.com]

• Hepatosplenomegaly

  A 46-year-old man presented with a high-grade fever, multiple lymphadenopathies, hepatosplenomegaly and human immunodeficiency virus (HIV) seropositivity, without severe immunosuppression. [ncbi.nlm.nih.gov]

  It manifests by fever, diffuse lymphadenopathy, hepatosplenomegaly, Involvement of the respiratory system and increased C-reactive protein. [orpha.net]

• Jaundice

  Additionally, MCD patients may suffer from peripheral edema, breathing difficulties and cough as well as jaundice. These symptoms result from an excess inflammatory response. [symptoma.com]

  CASE REPORT A 21-yr-old woman was admitted to our hospital in July, 2001 for evaluation of fever, jaundice and lymphadenopathy (LAP). [yumpu.com]

  Jun bean Park, Jin Hyeok Hwang, Haeryoung Kim, Hyung Sim Choe, Yu Kyeong Kim, Hong Bin Kim and Soo-Mee Bang, Castleman Disease Presenting with Jaundice: A Case with the Multicentric Hyaline Vascular Variant, The Korean Journal of Internal Medicine, 10.3904 [doi.org]

• Night Sweats

  He presented with fevers, dry cough, weight loss and drenching night sweats. Routine investigations were all unremarkable. [ncbi.nlm.nih.gov]

  The recurrent high fevers, night sweats, sky-high inflammatory markers—like C-reactive protein or erythrocyte sedimentation rate—are attributable to IL-6 overexpression. [targetedonc.com]

• Eruptions

  A 65-year-old man was admitted with relapsing and remitting fever, scattered skin eruptions and hepatosplenomegaly following combination antiretroviral therapy for his HIV infection. [ncbi.nlm.nih.gov]

  • A description is given of two patients with peculiar multiple skin eruptions, asymptomatic generalized lymphadenopathy, and polyclonal hypergammaglobulinemia. [jamanetwork.com]

  On the following day, she developed diarrhea and jaundice accompanied by pruritus, abdominal distension, lymphadenopathy and pruritic eruption. She had expenenced amenorrhea for four months prior to admission. [yumpu.com]

• Aura

  We report the case of a 47-year old Caucasian man who presented with subacute onset of constitutional symptoms, diffuse lymphadenopathy, and stereotyped spells involving olfactory aura, nausea, disorientation, and unresponsiveness. [ncbi.nlm.nih.gov]

Patients may claim remission and recurrence, but the disease may also follow a progressive course. Moreover, considerable shares of MCD patients present with comorbidities. AIDS and Kaposi sarcoma result from infections with HIV and HHV8, respectively. Accordingly, patients presenting with symptoms consistent with MCD should be queried as to a possible prior diagnosis of HIV or HHV8 infection. If such an infection has not been confirmed previously and subsequent diagnostic measures support the diagnosis of MCD, the respective tests should be ordered. Further entities commonly seen in MCD patients are POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and paraneoplastic pemphigus [9].

Generally, blood samples are obtained next. Laboratory findings typical of MCD are:

• Autoimmune hemolytic anemia
• Pancytopenia
• Polyclonal hypergammaglobulinemia
• Hypoalbuminemia
• Elevated C-reactive protein
• Enhanced levels of IL-6 and VEGF

Distinct diagnostic schemes have been proposed to assure a diagnosis of MCD [8] [10]. Those schemes are mainly based on the presence of fever and a determined number of additional clinical symptoms as well as on the detection of elevated C-reactive protein and other anomalies in blood biochemistry, but they have been shown to be of limited sensitivity [11]. Thus, it is strongly recommended to perform a histopathological analysis of a lymph node biopsy sample. Then, clinical, serological, laboratory and histological results should be interpreted as a whole.

The diagnostic workup of MCD patients further comprises the application of imaging techniques to precisely assess which lymph nodes are affected. Some of them may cause local mass effects besides contributing to systemic inflammation. In severe cases, symptomatic therapy is also required for complications like pleural effusion. Plain radiography is often utilized to visualize intrathoracic pathologies, but computed tomography scans may be more sensitive to this end. The latter is also employed for abdominal examinations.

• Thrombocytosis

  Multicentric Castleman's disease (MCD) is a polyclonal lymphoproliferative disorder that manifests as marked hyper-γ-globulinemia, severe inflammation, anemia, and thrombocytosis. [ncbi.nlm.nih.gov]

  Patients often have abnormal platelet counts, with some having thrombocytosis and others having thrombocytopenia. [doi.org]

  Typically there are also laboratory abnormalities: hypergammaglobulinemia, elevated inflammatory parameters, anemia, thrombocytosis, leucopenia, low serum albumin level, and, sometimes, elevated interleukin-6 (IL-6) [3]. [hindawi.com]

• Pleural Effusion

  Here, we report two cases of MCD associated with marked pleural effusion, ascites, and thrombocytopenia, and discuss the independence of the TAFRO syndrome (Castleman-Kojima disease). [ncbi.nlm.nih.gov]

Due to the crucial role of IL-6 in MCD pathogenesis, immunotherapy with monoclonal antibodies directed against this cytokine or its receptor is considered a first-line option. Siltuximab or tocilizumab may be administered to this end. Furthermore, thalidomide may be applied to suppress IL-6-mediated pro-inflammatory events. Bortezomib has been used with similar intentions. Rituximab is a monoclonal antibody directed against CD20, a surface antigen expressed by B cells, and is frequently used instead of the aforementioned compounds. Immunotherapy may be combined with corticosteroids - prednisone is commonly prescribed - or chemotherapeutics like cyclophosphamide or etoposide. Chemotherapy is generally reserved for severe cases and aggressive disease. Underlying viral infectious diseases may be treated with virostatics like cidofovir, ganciclovir or valganciclovir. Treatment recommendations have not yet been established and thus, therapeutic regimens encountered in the literature vary considerably [4]. Recurrence after cessation of drug therapy is likely and many patients require life-long maintenance therapy.

Contrary to UCD, surgical resection of affected lymphatic tissue is generally not an option promising cure of MCD. However, space-occupying lesions causing complications may be resected.

A patient's prognosis depends on their status regarding an infection with HIV and the subtype of MCD as assessed by histopathological analyses of tissue specimens. To date, MCD patients who test positive for HIV still have a poor prognosis. According to a retrospective study considering more than 400 cases of MCD, none of the HIV-positive patients presented with the hyaline vascular variant of the disease and their 3-year disease-free survival rate was nearly 28% [8]. Histopathologically similar cases in HIV-negative patients were associated with a disease-free survival rate of 46%.

The etiology of MCD is only poorly understood. The disease may be related to present infections with HIV and human herpesvirus-8 (HHV8, also referred to as Kaposi's sarcoma-associated herpesvirus). In fact, patients who suffer from immunodeficiency due to an infection with HIV are prone to an infection with HHV8, an opportunistic pathogen. Thus, it is not uncommon for MCD patients to test positive for both viruses. Dysregulated cytokine release has been identified as a major pathomechanism in MCD and it has been suggested that HIV and HHV8 may induce an inappropriate immune response [2]. In detail, persistent B cell activation due to virus replication in these cell populations, virus-mediated effects on lymphocyte differentiation as well as the production of a viral homologue of IL-6 by HHV8, all imply immunopathogenic mechanisms to be involved in the onset of MCD. Still, MCD patients may test negative for HIV and HHV8 [3]. This form of the disease is deemed idiopathic. Viral infections with pathogens distinct from those known to be associated with the disease, immune disorders as well as neoplasms have been suggested to account for these cases, but reliable evidence has not yet been provided to this end.

Recently, epidemiological data regarding MCD have been provided for the United States [4]. Although most cases were described in Caucasians, this observation may represent the demographic composition of the population rather than a racial predilection. People of African and Asian descent have also been diagnosed with the disease. About 60% of all patients were males. The median age of symptom onset was 55 years, but young adults were also shown to suffer from the disease. Of note, MCD has occasionally been reported in pediatric patients [5]. In some instances, MCD at a young age may be explained by immunodeficiency due to virus infection, but this does not apply to all such cases. Based on data collected, the overall incidence of MCD has been estimated to be 0.15 per million person-years. Prolonged survival of HIV patients due to improvements of therapy may eventually be accompanied by an increasing incidence of MCD [6].

Histopathologists distinguish three subtypes of CD, and analyses to this end are of prognostic value [7]. On one hand, lymphofollicular hyperplasia may be accompanied by prominent capillary hyalinization. The latter feature is why this form of the disease is known as hyaline vascular CD. In other patients, capillary hyalinization cannot be observed. Instead, plasma cells are arranged concentrically ("onion skin-like patterns") around the secondary follicles of lymph nodes. Moreover, plasma cells predominate in interfollicular regions, and consequently, this variant has been designated plasma cell MCD. A detailed characterization of B lymphocytes observed in tissue samples obtained from MCD patients allowed for the identification of a plasmablastic form of the disease. Plasma cells prevail in these specimens, too, but show an abnormal morphology with prominent nucleoli. Plasmablastic MCD behaves aggressively and is most common in HIV-positive patients.

The pathophysiological hallmark of MCD is hypercytokinemia, and patients generally present with increased serum concentrations of IL-6. This cytokine promotes B cell differentiation into plasma cells and stimulates the proliferation of this subpopulation of lymphocytes. Furthermore, IL-6 may trigger an acute phase response and fever as well as the vascular endothelial growth factor (VEGF). VEGF, in turn, induces angiogenesis. VEGF expression has been shown in lymph nodes of MCD patients, but could not be proven in samples obtained from a control group. Further studies are required, though, to clarify how VEGF is involved in MCD pathogenesis.

Because MCD is frequently associated with HIV infection, particularly AIDS; measures to prevent contracting the sexually transmitted disease may also reduce the individual risk of developing MCD. Such measures comprise the use of condoms and the reduction of sexual partners. Because the risk of HIV transmission is highest during anal sexual intercourse, men who have sex with men are considered a risk group, and this may indeed explain the observed predilection for males in studies regarding MCD. Implementation of needle-exchange programs may help to reduce HIV transmission among people abusing illicit drugs; patients who inject drugs should be advised to never share their needles with anyone.

In general, Castleman's disease refers to a rare disease primarily characterized by lymphadenopathy. It has first been described by the US-American pathologist Benjamin Castleman in 1954. Castleman and colleagues published a case report depicting a man with enlarged mediastinal lymph nodes [1]. Subsequent histopathological analyses revealed benign hyperplasia of these lymph nodes, while additional alterations of lymphatic tissues were not detected. Today, this entity is known as unicentric Castleman's disease (UCD). In contrast, patients may also develop polyadenopathy due to cytokine disorders and a systemic inflammatory response, and they are diagnosed with multicentric Castleman's disease (MCD). Whereas lymph node specimens obtained from either UCD or MCD patients share some common features, the latter are more prone to become symptomatic. Furthermore, MCD may progress to lymphoma and therapy is a major challenge. Besides monoclonal antibodies directed at cytokines produced in excess, chemotherapeutic drugs are administered in case of an aggressive lymphoproliferative disease. MCD patients may also receive antiviral treatment since viral infectious diseases seem to predispose for or effectively trigger this disorder. In fact, the outcome largely depends on the underlying disease, with patients infected with human immunodeficiency virus (HIV) having the poorest prognosis.

Multicentric Castleman's disease (MCD) is a rare systemic disorder of largely unknown etiology. Patients affected by MCD typically present with fatigue, fever, chills and night sweats, and may note swelling of lymph nodes in distinct regions of their body. Because lymph nodes are not necessarily palpable, the latter condition may only be recognized after imaging studies. Additionally, MCD patients may suffer from peripheral edema, breathing difficulties and cough as well as jaundice. These symptoms result from an excess inflammatory response. In detail, MCD is associated with dysregulated cytokine release, and these mediators stimulate subpopulations of immune cells to differentiate and proliferate. As has been indicated above, the precise trigger of these pathophysiological events remains unknown. However, there is a significant correlation between MCD and present infections with the human immunodeficiency virus (HIV) and/or human herpesvirus-8. The former causes AIDS, the latter is related to specific forms of cancer. Some MCD patients test negative for both pathogens, though.

Diagnosis of MCD involves clinical, laboratory and histopathologic studies. Thus, if a patient presents with symptoms consistent with MCD, their physician will obtain blood samples and perform a biopsy of an affect lymph node. Detailed examination of biopsy samples is of prognostic value since distinct subtypes of MCD are related to better or worse outcomes. In general, poorest outcomes are to be expected in HIV-positive patients. Therapy comprises immunomodulatory medication directed against excess cytokines, corticosteroids to reduce inflammation, chemotherapeutics to prevent further proliferation of lymphocytes, and antiviral therapy to treat the underlying disease. Some patients may require life-long maintenance therapy to avoid relapses. This is of particular importance since MCD patients are at relatively high risks of developing non-Hodgkin lymphoma, a type of malignant neoplasm originating from immune cells.

1. Castleman B, Towne VW. CASE records of the Massachusetts General Hospital Weekly Clinicopathological Exercises: Case 40011. N Engl J Med. 1954; 250(1):26-30.
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3. Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014; 123(19):2924-2933.
4. Robinson D, Jr., Reynolds M, Casper C, et al. Clinical epidemiology and treatment patterns of patients with multicentric Castleman disease: results from two US treatment centres. Br J Haematol. 2014; 165(1):39-48.
5. Leroy S, Moshous D, Cassar O, et al. Multicentric Castleman disease in an HHV8-infected child born to consanguineous parents with systematic review. Pediatrics. 2012; 129(1):e199-203.
6. Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman's disease. Ann Oncol. 2009; 20(4):775-779.
7. Reddy D, Mitsuyasu R. HIV-associated multicentric Castleman disease. Curr Opin Oncol. 2011; 23(5):475-481.
8. Talat N, Schulte KM. Castleman's disease: systematic analysis of 416 patients from the literature. Oncologist. 2011; 16(9):1316-1324.
9. Gérard L, Bérezné A, Galicier L, et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial. J Clin Oncol. 2007; 25(22):3350-3356.
10. Uldrick TS, Polizzotto MN, Yarchoan R. Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Curr Opin Oncol. 2012; 24(5):495-505.
11. Bower M, Pria AD, Coyle C, Nelson M, Naresh K. Diagnostic criteria schemes for multicentric Castleman disease in 75 cases. J Acquir Immune Defic Syndr. 2014; 65(2):e80-82.