RESUMO
Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert-confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6-directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6-directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.
Assuntos
Hiperplasia do Linfonodo Gigante , Humanos , Rituximab/uso terapêutico , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Corticosteroides/uso terapêuticoRESUMO
Mass spectrometry-based techniques now enable the unbiased identification of proteins in complex mixtures including proteins isolated from cells and tissues. These powerful tools permit near-complete annotation of proteins expressed in cells, tissues or organs. Further, these techniques permit the interrogation of the numerous posttranslational modifications that govern cell-specific responses to signaling cues and underlie the functional heterogeneity of cellular composition and contribute to biological complexity. Parallel developments in technologies such as mass cytometry and multicolor ion-beam imaging which permit multi-parameter detection of numerous proteins at the single-cell and in situ level respectively, are poised to radically impact our understanding of the functional and translational importance of proteins in hematologic conditions. Importantly, the field of proteomics is poised to realize the immensely powerful opportunities in integration with genomic information that is being discovered at an unprecedented pace for many hematologic conditions.
Assuntos
Genômica/métodos , Hematologia/métodos , Espectrometria de Massas/métodos , Proteômica/métodos , HumanosRESUMO
Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.
Assuntos
Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/terapia , Ensaios Clínicos como Assunto , Estado Terminal/terapia , Gerenciamento Clínico , Medicina Baseada em Evidências , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.
Assuntos
Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/etiologia , Herpesvirus Humano 8 , Consenso , Diagnóstico Diferencial , Humanos , Internacionalidade , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Call centres can improve the effectiveness of health services by helping reduce access barriers associated with stigma and geography. This project aimed to develop and pilot a standardised evaluation framework to assess Marie Stopes International reproductive health call centres. METHODS: Consultations were held with staff from the 14 existing international call centres to gauge current monitoring and evaluation processes, identify gaps, and establish evaluation needs. The draft framework was then piloted in the Marie Stopes Mexico call centre using client and provider surveys, mystery callers and a review of call centre records. RESULTS: A flexible framework was developed to allow call centres to measure the effectiveness of services offered. Nineteen indicators were developed to assess access, equity, quality and efficiency. The pilot found pre-defined ranges for indicators of access were not appropriate for a high-functioning call centre that was already achieving nearly 100% compliance. Several indicators could not be measured due to a lack of routine data collection systems. CONCLUSIONS: A standardised evaluation framework will allow comparisons over time and between call centres in different countries. Future assessments could be improved by establishing routine, reliable data collection systems prior to framework implementation. This is one of the first attempts to standardise the evaluation of a reproductive health call centre and establishes a method by which they can be monitored, and thus improved, over time.