CD20, generalidades básicas-moleculares y su posible relación como marcador de mal pronóstico en leucemia / CD20, basic-molecular generalities, and its possible relationship as a marker of poor prognosis in leukemia

CD20 es una proteína transmembranal expresada en la superficie del linfocito B y desempeña un papel muy importante en su desarrollo y diferenciación. Se expresa en la gran mayoría de neoplasias de células B, como en la leucemia linfoblástica aguda (LLA). Se recopiló información sobre la estructura biológica y molecular del marcador CD20 y su mecanismo de regulación, para mejorar el entendimiento sobre su función dentro de la célula, el efecto que ejerce como marcador de mal pronóstico cuando se encuentra expresado en pacientes adultos diagnosticados con LLA y las ventajas de ser utilizado como blanco terapéutico en esta patología.

CD20 is a transmembrane protein expressed on the surface of the B lymphocyte and plays a significant role in its development and differentiation. It is expressed in most B-cell neoplasms, such as Acute Lymphoblastic Leukemia (ALL). Information was collected on the biological and molecular structure of the CD20 marker and its regulation mechanism to improve the understanding of its function within the cell, the effect it exerts as a marker of poor prognosis when expressed in adult patients diagnosed with ALL, and the advantages of being used as a therapeutic target in this pathology.

Linfomas no Hodgkin indolentes y terapia anti-CD20: una revisión de la literatura / Indolent non-Hodgkin's lymphomas and anti-CD20 therapy: a literature review

Introducción: Los linfomas no Hodgkin indolentes se destacan por el reto que suponen desde el punto de vista terapéutico. La introducción de la terapia con rituximab, un anticuerpo monoclonal que se une al antígeno CD20 de la membrana de los linfocitos B, revolucionó los tratamientos hasta ese momento y abrió el camino para el desarrollo de otros anticuerpos monoclonales anti-CD20. Objetivo: Describir las características generales de los linfomas no Hodgkin indolentes y de los anticuerpos monoclonales anti-CD20, así como el rol de la terapia anti-CD20 en dichas enfermedades. Métodos: Se realizó una revisión de la literatura publicada en los últimos 20 años, disponible en los repositorios: Scielo, Scopus, Pubmed/Medline, ScienceDirect y Mediagraphic. Se emplearon para elaborar este manuscrito 35 documentos, de ellos 80 por ciento correspondieron a los últimos 5 años. Conclusiones: La sólida evidencia científica, acumulada durante las últimas dos décadas, respalda el uso clínico de los anticuerpos monoclonales anti-CD20 en el tratamiento de los linfomas no Hodgkin indolentes. El uso efectivo de estos fármacos como agentes únicos o combinados con quimioterapia demuestran su versatilidad terapéutica(AU)

Introduction: Indolent non-Hodgkin's lymphomas are notable for the challenge they pose from a therapeutic point of view. The introduction of rituximab, a monoclonal antibody that binds to the CD20 antigen of the B-lymphocyte membrane, revolutionized treatments up to that time and opened the way for the development of other anti-CD20 monoclonal antibodies. Objective: To describe the general characteristics of indolent non-Hodgkin's lymphomas and anti-CD20 monoclonal antibodies, as well as the role of anti-CD20 therapy in these diseases. Methods: A review of the literature published in the last 20 years, available in the repositories: Scielo, Scopus, Pubmed/Medline, Science Direct and Mediagraphic, was performed. Thirty-five papers were used to prepare this manuscript, 80 percent of which corresponded to the last 5 years. Conclusions: Strong scientific evidence, accumulated over the last two decades, supports the clinical use of anti-CD20 monoclonal antibodies in the treatment of indolent non-Hodgkin's lymphomas. The effective use of these drugs as single agents or in combination with chemotherapy demonstrates their therapeutic versatility(AU)

Clinicopathological features of mature T/NK cell lymphoma with aberrant CD20 or CD79α expression / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics and prognosis of mature T/NK cell lymphomas with aberrant CD20 or CD79α expression. Methods: A retrospective analysis of 641 cases of mature T/NK cell lymphoma diagnosed from January 2014 to December 2020 was performed, and 14 cases of CD20-positive and one case of CD79α-positive mature T/NK-cell lymphoma were identified. Histological examination, immunohistochemical characterization, in situ hybridization for Epstein-Barr virus encoded early RNA (EBER), and PCR testing for immunoglobulin and T cell receptor (TCR) gene rearrangements were performed. Clinicopathological characteristics of these lymphomas were analyzed. Results: There were 13 males and 2 females, with a median age of 56 years. There were 8 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 3 cases of extranodal NK/T-cell lymphoma, nasal type (ENKTCL), 2 cases of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) and 2 cases of angioimmunoblastic T-cell lymphoma (AITL). Twelve cases were stage Ⅲ or Ⅳ lymphomas. The prognosis was overall poor. The histology, immunophenotype and TCR gene rearrangement were not significantly different from the corresponding types of lymphoma. Ki-67 proliferation index was over 70% in all cases. The expression of CD20 or CD79α was weak and heterogeneous. All 15 case of Ig gene rearrangement were polyclonal. Conclusions: Mature T/NK cell lymphoma with abnormal expression of CD20 or CD79α is rare, commonly found in advanced stage, and associated with poor prognosis. The expression of CD20 or CD79α in these cases is weaker than the corresponding mature T/NK cell lymphomas, while its proliferation index is higher. Histomorphology, extensive immunoprofiling and molecular detection are required for accurate diagnosis.

Uso clínico do rituximabe em doenças autoimunes / Clinical use of rituximab for autoimmune diseases

Doenças autoimunes são doenças universais, e os diagnósticos e tratamentos primários são habitualmente iniciados por clínicos em enfermarias ou ambulatórios, antes de serem encaminhados a especialistas. Além disso, pacientes em uso de biológicos internados em hospitais gerais têm sido cada vez mais frequentes na prática clínica. Conhecer o perfil de segurança, as indicações e os efeitos colaterais dessas drogas deve ser preocupação dos clínicos. Neste trabalho, foi realizada revisão de literatura sobre terapia biológica com rituximabe no tratamento das principais doenças autoimunes sistêmicas da prática clínica: artrite reumatoide, lúpus eritematoso sistêmico, vasculites relacionadas aos anticorpos anticitoplasma de neutrófilo, púrpura trombocitopênica imune e espondilite anquilosante. (AU)

AutoimmunAutoimmune diseases are universal diseases and primary diagnosis and treatment are typically initiated by internists in wards or outpatient clinics before being referred to specialists. In addition, patients on use of biologicals hospitalized in general hospitals have been increasingly common in clinical practice. Knowing the safety profile, the indications, and the side effects of these drugs should be a concern for the internists as well. In this study, the literature review was performed on biological therapy with Rituximab for treating the main systemic autoimmune diseases of clinical practice: rheumatoid arthritis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitides, immune thrombocytopenic purpura, and ankylosing spondylitis. (AU)

Linfomas de estirpe B: bases para su entendimiento / Line B lymphomas: understanding their bases

Propósito de la revisión: el objetivo de la revisión es delinear la fisiopatología de los linfomas de estirpe B.Buscamos reportes endonde se incluyela descripción del origen de los Linfomas B para una mejor comprensión de esta patología, a la luz de los avances en las diferentes áreas. Recientes hallazgos: El Grupo Euroflow ha publicado una lista de paneles de Expresión de Antígenos de Superficie en Linfoma no Hodgkin, cuya lista se presenta en este artículo. Extracto: Las neoplasias hematológicas han tenido grandes avances en los últimos años en varios campos, evolucionando desde la identificación citológica, pasando por su caracterización inmunofenotípica por medio de la Citometría de Flujo e Inmunohistoquímica y llegando a la caracterización molecular, iniciando por Técnicas de Cariotipo Convencional, continuando por técnicas de Inmunohibridación in situ y actualmente con la identificación molecular por medio de la Secuenciación de Nueva Generación. Esta es la razón por la que los sistemas de estadificación han ido evolucionando también, siendo el que está al momento en vigencia el propuesto por la Organización Mundial de la Salud en el año 2016.Los linfomas constituyen un grupo heterogéneo de neoplasias hematológicas con un amplio espectro de presentación clínica, cuyo origen se encuentra en los precursores de linfoides y que afectan a los diversos órganos linfoides. De estos, los linfomas dela línea B son los más comunes, motivo de esta revisión

Purpose of the review: the objective of the review is to delineate the pathophysiology of B-line lymphomas. We are looking for reports that include a description of the origin of B-lymphomas for a better understanding of this pathology, in light of advances in the different areas. Recent Findings: The Euroflow Group has published a list of Surface Antigen Expression panels in Non-Hodgkin Lymphoma, the list of which is presented in this article. Extract: Hematological neoplasms have had great advances in recent years in several fields, evolving from cytological identification, passing through their immunophenotypic characterization through Flow Cytometry and Immunohistochemistry and reaching molecular characterization, starting with Conventional Karyotype Techniques , continuing with in situ Immunohybridization techniques and currently with molecular identification through New Generation Sequencing. This is the reason why staging systems have also evolved, the one currently in force being the one proposed by the World Health Organization in 2016. Lymphomas constitute a heterogeneous group of hematological neoplasms with a wide spectrum of clinical presentation, originating from lymphoid precursors and affecting the various lymphoid organs. Of these, line B lymphomas are the most common, which is the reason for this review

CD20 is not a poor prognostic factor for childhood B-lineage acute lymphoblastic leukemia with high white blood cell count / 中国当代儿科杂志

OBJECTIVE@#To study the significance of CD20 combined with white blood cell (WBC) count at diagnosis in the prognosis assessment in children with B-lineage acute lymphoblastic leukemia (ALL).@*METHODS@#A retrospective analysis was performed on the medical data of 821 B-ALL children who were treated with CCLG-ALL2008 regimen from April 2008 to April 2015. Their survival status was followed up.@*RESULTS@#Among the 821 children, 547 (66.6%) were negative, while 274 (33.4%) were positive for CD20 expression. Among 694 children with WBC50×10/L (higher WBC count), the 5-year EFS rates was 64.3%±7.7% and 53.7%±5.5% for CD20 positive and negative patients respectively (P=0.135); the 5-year OS rate was 81.4%±6.4% and 58.6%±5.6% for CD20 positive and negative patients respectively (P=0.022); CD20 positive expression was an independent protective factor for OS (HR=0.367, P=0.016).@*CONCLUSIONS@#In children with B-ALL who are treated with CCLG-ALL2008 regimen, those with CD20 positive expression in lower WBC count at diagnosis have a poor prognosis; however, those with CD20 positive expression in higher WBC count at diagnosis have a better long-time survival.

Obtención de una versión IgG1 de ratón del rituximab para detectar la molécula CD20 humana / Obtaining a mouse IgG1 version of rituximab to detect the human CD20 molecule

Introducción: El rituximab, anticuerpo quimérico que reconoce la molécula CD20 humana, se ha utilizado en el tratamiento de diversos trastornos linfoproliferativos de células B. Para la selección de los potenciales beneficiarios del tratamiento con rituximab se han desarrollado técnicas que, mediante el uso de anticuerpos monoclonales, detectan la presencia del CD20 en los linfocitos de estos pacientes. Objetivo: Obtener y caracterizar un anticuerpo recombinante IgG1 de ratón específico para la molécula CD20 humana, que contenga las regiones variables del anticuerpo rituximab. Métodos: Para la expresión estable del anticuerpo recombinante se empleó la transducción lentiviral de células de embrión de riñón humano (HEK293). La caracterización inmunoquímica del anticuerpo se realizó por la técnica de Western Blot y su capacidad de reconocimiento de la molécula CD20 humana se evaluó por citometría de flujo e inmunohistoquímica. Resultados: Se obtuvo el anticuerpo 1F5 que reconoce, por citometría de flujo, la molécula CD20 en líneas celulares humanas de origen linfoide, así como en células de sangre periférica de humanos sanos y pacientes con trstornos linfoproliferativos de células B. Sin embargo, la técnica de inmunohistoquímica solo permitió detectar con este anticuerpo la molécula CD20 en tejidos frescos, no así en los embebidos en parafina. Conclusiones: Este trabajo sugiere las potencialidades del uso del anticuerpo 1F5 para las mediciones de la expresión de CD20 por citometría de flujo en pacientes con leucemias B o linfomas B avanzados en fase de leucemización. Esto complementaría los estudios para la selección apropiada de pacientes para el tratamiento con el rituximab(AU)

Introduction: Rituximab, chimeric antibody specific for human CD20 molecule, has been widely used in the treatment of several B-cell linfoproliferative disorders. For the selection of patients with the greatest potential to benefit from the therapy with rituximab, a number of techniques using monoclonal antibodies have been developed to detect the CD20 molecule. Objective: To obtain and to characterize a mouse IgG1 recombinant antibody, specific for human CD20, that contains the variable regions of rituximab. Methods: The lentiviral transduction of human embryonic kidney cells (HEK293) was used for the stable expression of the recombinant antibody. The immunochemical characterization of the antibody was performed by Western Blot and the recognition of CD20 was evaluated by immunohistochemistry and flow cytometry. Results: We generated the antibody 1F5, able to recognize by flow cytometry the CD20 molecule expressed on lymphoid human cell lines, as well as peripheral blood mononuclear cells from healthy donors and patients with B-cell lymphoproliferative disorders. However, 1F5 antibody detected the CD20 molecule on fresh tissues, but not on formalin-fixed paraffin embedded tissues,by immunohistochemistry. Conclusions: This work suggests the potential use of 1F5 antibody for the measurement of CD20 expression by flow cytometry in patients with B-cell leukemias or B-cell lymphomas in phase of leukemization. This could complement the studies to ensure the appropriate selection of patients for the treatment with rituximab(AU)

Clinical Analysis of B-CLPD with Cytopemia as the Predominant Characteristic / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics and therapeutic responte of patients with B-CLPD mainly manifested as cytopenia, so as to deeply understand this disease.@*METHODS@#The clinical data of 13 B-CLPD patients with hematocytopenia as main manifestation, and the absolute count of lymphocytes＜5×10/L, absence of hepatosplenic lymph-nodes and extramedullary invasion tin our department fron 2003 to 2018 were analyzed retrospectively. The clinical characteristics, therapeutic efficacy and adverse reactions of 3 patients were summarized.@*RESULTS@#The median age of patients was 59 (43-76) years old, the median of lymphocyte was 1.86 (0.69-4.8) ×10/L, the levels of LDH and β2-microglubulin were normal in most patients, the monolineage and multilencage hematopoietic failure of different degrees existed in most all patients. The lymphocyte ratio in patients was 18.5%-94.0%, CD20 was positive in all patients, and yet the CD5-positive and CD-negative existed in 7 and 6 cases respectively. There was no significant difference in ratio of lymphocyte invasion among different immunophemtype. The FISH detection showed that there were no high risk genetic types. 92.3% of patients received rituximab treatment, most of them received chemotherapy of rituximab combined with C0P/CHOP like regimen, only 2 patients received fludarabine for comparatively short course. The analysis indicated that 8 out of 13 patients showed a certain theropeutic efficacy, however the drug-related hematopoietic suppression occurred in both 2 patients treated with fludarabin.@*CONCLUSIONS@#The B-CLPD accompanied with hematocytopenia often displays bone marrow hypohematopoiesis of different degree and easily confuses with the congenital and acquired hemotopoietic faiture diseases. The rituximab treatment may be more appropreate for these patients, but for patients received chemotherapy containing fludarabin, the persistant hematopoietic failure must be especially watched out.

Ofatumumab monoclonal antibody affinity maturation through in silico modeling

Background: Ofatumumab, an anti-CD20 mAb, was approved in 2009 for the treatment of chronic lymphocytic leukemia. This mAb acts through immune-mediated mechanisms, in particular complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by natural killer cells as well as antibody-dependent phagocytosis by macrophages. Apoptosis induction is another mechanism of this antibody. Computational docking is the method of predicting the conformation of an antibody-antigen from its separated elements. Validation of the designed antibodies is carried out by docking tools. Increased affinity enhances the biological action of the antibody, which in turn improves the therapeutic effects. Furthermore, the increased antibody affinity can reduce the therapeutic dose of the antibody, resulting in lower toxicity and handling cost

Methods: Considering the importance of this issue, using in silico analysis such as docking and molecular dynamics, we aimed to find the important amino acids of the Ofatumumab antibody and then replaced these amino acids with others to improve antibody-binding affinity. Finally, we examined the binding affinity of antibody variants to antigen

Results: Our findings showed that variant 3 mutations have improved the characteristics of antibody binding compared to normal Ofatumumab antibodies. Conclusion: The designed anti- CD20 antibodies showed potentiality for improved affinity in comparison to commercial Ofatumumab

Application Value of Immunohistochemistry and Bone Marrow Morphology Detection in the Diagnosis and Clinical Staging of Non-Hodgkin's Lymphoma / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the application value of immunohistochemistry detection and bone marrow morphology analysis in the diagnosis and clinical staging of non-Hodgkin's lymphoma.</p><p><b>METHODS</b>Sixty-four cases of non-Hodgkin's lymphoma were selected in our hospital and the immunohistochemistry detection of pathologic specimens was perforemed by related monoclonal antibody and the bone marrow morphology was also examined.</p><p><b>RESULTS</b>The positive rate of antibody CD79a on B cell lymphoma was 84.62%, and CD20 was 91.43%; the positive rate of antibody CD45RO on T cell lymphoma was 87.50%, and 88.89% of CD3. The bone marrow involvement was found in 10 cases (15.63%), 8 cases(12.50%) progressed to lymphoma - leukemia period; lymphoma cells were lower than 5% in 20 cases (31.25%).</p><p><b>CONCLUSION</b>Immunohistochemistry detection can help to define the type of T or B cell lymphoma in patients with non-Hodgkin's lymphoma, the bone marrow morphology analysis can clear whether the patients with non-Hodgkin's lymphoma suffered from bone marrow involvement and whether developed to lymphoma- leukemia period. These methods possess more high value in clinical application.</p>

CD20 role in pathophysiology of Hodgkin's disease / O papel do CD20 na fisiopatologia da doença de Hodgkin

Summary Hodgkin's lymphoma (HL) is a tumor comprising non-malignant and malignant B-cells. Classical HL expresses CD15+ and CD30+ antigens, and 20 to 40% of patients are CD20+. This antigen is a ligand free protein present in B lymphocyte cells and its function is not well known. Some studies suggest that expression of CD20 may play a major role in Hodgkin's disease pathophysiology and may affect the patients' treatment prognosis, as well as relapse and refractory response. In the past few years, development of monoclonal anti-CD20 antibodies changed drastically the treatment for non-Hodgkin lymphomas in which CD20 is expressed. HL treatment is essentially composed of radiotherapy and chemotherapy; however, monoclonal anti-CD20 antibodies applicability is not well delimitated due to lack of information about clinical outcomes with anti-CD20 monotherapy or combined drug therapy using a classic regimen, as well as about CD20 pathophysiology mechanisms in B-cells tumors. The objective of our review is to discuss CD20 function in Hodgkin's lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients' prognostic.

Resumo O linfoma de Hodgkin (LH) é um tumor composto por células B não malignas e malignas. O LH clássico expressa antígenos CD15+ e CD30+, mas apenas cerca de 20 a 40% dos pacientes expressa também antígeno CD20. Este antígeno é uma proteína sem ligante presente nas células de linfócitos B cuja função não é bem conhecida. Alguns estudos sugerem que a expressão de CD20 pode ter um papel importante na fisiopatologia da doença de Hodgkin e pode afetar o prognóstico dos pacientes ao tratamento, bem como recaída e refratariedade. Nos últimos anos, o desenvolvimento de anticorpos monoclonais anti-CD20 mudou drasticamente o tratamento para linfomas não Hodgkin em que o CD20 é expresso. O tratamento do LH é composto essencialmente de radio e quimioterapia; no entanto, o espaço dos anticorpos monoclonais anti-CD20 não está bem delimitado em decorrência de: falta de informação sobre o desfecho clínico, seja na monoterapia com anti-CD20, seja na terapêutica combinada com o regime clássico; falta de informação sobre os mecanismos de fisiopatologia CD20 em tumores de células B. O objetivo desta revisão é discutir sobre a função do CD20 no desenvolvimento do linfoma de Hodgkin, sua influência na evolução da doença e os resultados, bem como os efeitos sobre terapêutica e prognóstico dos pacientes.

Eficacia y seguridad del uso de tofacitibini en el tratamiento de artritis reumatoide refractaria a Anti-TNF y Anti-CD20 / Efficacy and safety of the use of tofacitibini in the treatment of rheumatoid arthritis refractory to Anti-TNF and Anti-CD20

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad tofacitinib en pacientes con artritis reumatoide con falla a tratamiento con anti-TNF y anti-CD20. Aspcetos Generales: La artritis reumatoide (AR) es un tipo de poliatritis periférica de naturaleza inflamatória y simétrica. Esta condición suele llevar a una deformación de las articulaciones a través de la erosión de cartilagos y hesos. La ausencia de un tratamiento eficaz, la inflamación y la destrucción de las articulaciones lleva la pérdida de las funciones motoras, y por tanto a la incapacidad de llevar a cabotareas cotidians, e incluso a dificuldades en el ámbito laboral. Tecnología Sanitaria de Interés: El tratamiento de AR incluye como prímera linea el uso de glucocorticoides y fármacos modificadores de la enfermedad (FARMEs) sintético. Si no se obtiene una respuesta adecuada con estos FARMEs sintéticos, es recomendable pasar al uso de agentes biológico, siendo los anti-TNF considerados como la primera opición por la alta tasa de respuesta asoiada a su uso. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una búsqueda de literatura publicada sobre tofacitinib en el tratamiento de Artritis Reumatoide en las bases de datos: medline y Tripdabase. Adicionalmente, se realizaron búsquedas en los portales web de entidades que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica: The Cochrane Library, National Institute for Helath and Care Excellence (NICE) del Reino Unido, American College of Rheumatology, European League Against Rheumatism, Revista Brasileira de Reumatologia, Canadian Agency for Drugs and Technologies in Health. RESUlTADOS: Sinopsis de la Evidencia: Guías de práctica Clínica: Se identificó una GPC de NICE del 2015 la cual redirecciona al lector hacia las evaluaciones de tecnología sanitaria publicadas por NICE sobre los diferentes agentes en el tratamiento de AR, las cuales fueron revisadas e incluidas en los resultados cuando fue pertinente. Evaluaciones de tecnología santiaria: Se incluyó en los resultados una revisión rápida de Canadian Agency for Drugs and Technologies in Health del 2015. Una ETS de NICE sobre tofacitinib se encuentra en desarrollo y se espera que esta sea publicada en el 2018. Revisiones sistemáticas con o sin meta-análisis: Se incluyó una revisión sistemática con meta-análisis de ensayos clínicos controlados, aleatorizados y doble ciego del 2013, y un análisis de data agregada del 2015. Adicionalmente, se incluyeron tres estudios que evaluaron únicamente seguridad: un análisis de dataagregada del 2014, un meta-análisis del 2015, y un análisis del 2017. Ensayos clínicos aleatorizados de fase III. Se incluyó en ECA de fase III del 2013. Adicionalmente, como sugerencia del especialista, se agregó un ECA de fase III del 2012. Resumen de congreso: A sugerencia del especialista se incluyó en los resultados un resumen del congreso del 2016. CONCLUSIONES: A la fecha no se han publicado ensayos clínicos aleatorizados del uso de tofacitinib en una población de pacientes con falla a tratamiento (primaria, secundaria o intolerancia) tanto a anti-TNFs como a anti-CD20. Las GPC identificadas presentan recomendaciones heterogéneas sobre el uso de tofacitinib. A pesar de ello, se puede concluir que, de acuerdo con las GPC, tofacitinib es considerado una alternativa tanto en pacientes que han fallado a tres o más tratamientos biológicos, como en aquellos que han fallado a uno; sin embargo, la mayoria de las GPC concuerdan en que el uso de tofacitinib se debe limitar a aquella población que ha agotado las opciones disponibles de tratamiento biológico, debido principalmente a la escasa información sobre el perfil de seguridad de tofacitinib y su efectos a largo plazo. Debido a que no es clara la relación riesgo/benefício y que existen otras alternativas que han probado ser eficaces para la misma condición (pacientes con AR con respuesta inadecuada a FARMEs biológicos) disponibles en el mercado peruano; a la fecha no se cuenta con evidencia que sustente que el uso de tofacitinib en la población de pacientes con respuesta inadecuada a mas de dos tratamientos biológicos suponga un benefício adicional al tratamiento utilizado actualmente, ni que se trate de un medicamento seguro para los pacientes. Asimismo, vale resaltar que las GPC internacionales identificadas mencionan otras posibles alternativas para la condición mencionada, e incluso algunas de ellas recomiendan otras alternativas por encima de tofacitinib, en línea con la preocupación ralacionada a su perfil de seguridad, y recomiendan reservar su uso únicamente para la población que ha agotado las opciones de tratamiento biológico disponibles en el mercado. El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de tofacitinib en pacientes con AR que han fallado a tratamiento con anti-TNF y con anti-CD20.

Pemphigus foliaceus treated with rituximab monotherapy

In pemphigus foliaceus (PF), immunoglobulin G (IgG) autoantibodies directed against desmoglein-1 (Dsg-1), a cell adhesion molecule expressed mainly in the granular layer of the epidermis, are responsible for the intercellular widening between desmosomes resulting in intraepidermal blisters. Rituximab is a chimeric monoclonal antibody that by binding specifically to the transmembrane antigen CD20 found on the surface of normal and malignant B cells, leads to B-cell depletion. We report a 19-year-old Filipino woman with PF and controlled idiopathic thrombocytopenia purpura, initially treated with high-dose prednisone and azathioprine. Due to rapid PF progression with associated moderate reactive depression, rituximab was added to the treatment regimen with prompt improvement of lesions and clearance after five months. Five years later, lesions recurred with erythematous, dry, scaly plaques on both breasts, axillae, and on the scalp, associated with moderate to severe intermittent pruritus. After the first of a series of four weekly infusions, rituximab monotherapy resulted in immediate and sustained clearance up to 22 months. In parallel with skin clearance, serum CD19 and CD20 B cells decreased to almost zero after the first infusion, to zero after the second, while the decrease of Dsg-1 levels was more gradual, and down to normal after four months.We offer this case report to show that rituximab can be given as a first-line monotherapy option for indications similar to ours such as drug reactions (steroid-induced depression) or a history of recalcitrant PF to the usual medications; and to suggest using CD19 and CD20 in addition to the desmoglein levels to monitor disease activity and molecular change from which to learn how to continue to monitor for disease activity after clearance.

Diffuse large B-cell lymphoma with aberrant expression of CD56: a clinicopathologic and immunohistochemical study / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features and significance of aberrant CD56 expression in diffuse large B-cell lymphoma (DLBCL).</p><p><b>METHODS</b>The clinical and pathologic profiles of 10 cases of DLBCL with aberrant expression of CD56 were investigated. Immunohistochemical staining, in-situ hybridization for Epstein-Barr virus encoded RNA and gene rearrangement for IgH and Igκ were carried out.</p><p><b>RESULTS</b>There were 6 male and 4 female patients. The medium age of patients was 46 years. All of them presented with extranodal lymphoma involvement, with gastrointestinal tract being the commonest site (5/10). Histologic examination showed that most of the atypical lymphoid cells were centroblast-like and demonstrated a diffuse growth pattern. Apoptosis and necrosis were identified in some cases. Immunohistochemical study showed that the tumor cells were positive for CD20 or CD79α and aberrantly expressed CD56. Five cases had the GCB phenotype while the remaining cases had the non-GCB phenotype, according to Hans classification. Bcl-6 was positive in most cases (9/10). All cases showed a high proliferation index by Ki-67. The tumor cells were negative for CD3ε, CD138 and granzyme B. In-situ hybridization for Epstein-Barr virus encoded RNA was performed in 7 cases and none of them showed positive signals. IgH gene rearranged bands were detected in 4 cases (4/6) and Igκ was detected in 3 cases (3/6). Follow-up data were available in 8 patients. Two patients died of disease progression within 5 to 13 months after diagnosis and the other 6 patients were alive 8 to 60 months after therapy.</p><p><b>CONCLUSIONS</b>DLBCL with aberrant expression of CD56 is rare. Most of them present with extranodal involvement, show high frequency of bcl-6 expression and high proliferation index. The patients often have good response to chemotherapy.</p>

Prognostic Implication of Semi-quantitative Immunohistochemical Assessment of CD20 Expression in Diffuse Large B-Cell Lymphoma

BACKGROUND: Immunohistochemical demonstration of CD20 in diffuse large B-cell lymphoma (DLBCL) is prerequisite not only for the diagnosis but also for assigning patients to rituximab-containing chemotherapy. However, little is known about the impact of abundance of CD20 expression assessed by immunohistochemistry on the clinical outcome of DLBCL. We performed a semi-quantitative immunohistochemical analysis of CD20 expression in DLBCL to examine the prognostic implication of the level of CD20 expression. METHODS: Pre-treatment diagnostic tissue samples from 48 DLBCL patients who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen were represented in a tissue microarray and immunostained for CD20. The relative abundance of CD20 expression was semi-quantitatively scored using a web-based ImmunoMembrane plug-in. Receiver operating characteristic curve analysis was used to determine a prognostically relevant cut-off score in order to dichotomize the patients into CD20-high versus CD20-low groups. RESULTS: The levels of CD20 expression were heterogeneous among the patients, with a wide and linear distribution of scores. Patients in CD20-low group showed significantly poor clinical outcome. CONCLUSIONS: The levels of CD20 expression in DLBCL are heterogeneous among the patients with DLBCL. A subgroup of the patients with CD20 expression levels below the cut-off score showed poor clinical outcome.

Immunohistochemical evaluation of CD20 expression in patients with multiple myeloma

Objective: CD20 expression was reported at different rates in patients with multiple myeloma. The importance of this B-cell antigen for plasma cells is still unknown. This study aimed to investigate CD20 expression of myeloma cells in bone marrow, and any relationship between the stage of disease, isotype and clinical features. Methods: Sixty-one patients who were admitted to the hematology clinic of the Adnan Menderes Medical School with the diagnosis of multiple myeloma according to the criteria of the "International Myeloma Working Group" were enrolled in this study. Age, gender, Durie-Salmon stage, history of autologous hematopoietic stem cell transplantation, and the distribution pattern and positivity of CD20 expression on multiple myeloma cells in bone marrow were evaluated. The Mann-Whitney U and chi-square tests were used for statistical analysis with a p-value < 0.05 being accepted as statistically significant. Results: Thirty patients (48.9%) had positive scores for CD20 with the distribution pattern being most likely interstitial in 55.6% of the cases. There was no statistically significant difference between immunohistochemical positivity for CD20 expression on multiple myeloma cells, immunoglobulin type, and the stage of disease. Conclusion: The combination of immunohistochemical studies with flow cytometry may reveal the importance of CD20 positivity in patients with multiple myeloma more clearly. .

Development of a novel reporter gene method for determination of ADCC potency of anti-CD20 monoclonal antibody / 药学学报

The biological activity of ADCC by anti-CD20 monoclonal antibody was determined by BioGlo™ Luciferase Assay System using Jurkat/NFAT-luc+FcγRIIIa cell line as effector cell and WIL2-S cell line as target cell. The developed method was verified for specificity, precision and accuracy. Anti-CD20 monoclonal antibody showed a dose-response mode by the developed method, and the determination result complied with the following four-parameter equation: y = (A-D)/[1 + (X/C)(B)] + D. The optimized parameters of the method were determined including the antibodies diluted concentration (18,000 ng·mL(-1)), dilution rate (1:5), the ratio of effector cell and target cell (6:1), and induction time (6 h). The values of eight independent tests have passed a statistical test for curve regression analysis, linear or parallelism, which showed the method possessed good specificity. Four different dilute groups of recovery rates sample were determined for 3 times, and the result showed mean relative potencies of (44.39±3.93)%, (72.74±2.78)%, (128.28±7.01)% and (168.19±2.70)% respectively, with a variation coefficient of less than 10%, and the recoveries of (88.78±7.85)%, (96.99±3.70)%, (102.63±5.61)% and (112.12±1.80)% respectively. A novel reporter gene method for determination of biological activity of ADCC by anti-CD20 monoclonal antibody was successfully developed, which showed strong specificity, good reproducibility and high accuracy, and might be used routinely.

Gastric Perforation Caused by Primary Gastric Diffuse Large B Cell Lymphoma / 대한소화기학회지

Spontaneous gastric perforation is a rare complication of gastric lymphoma that is potentially life threatening since it can progress to sepsis and multi-organ failure. Morbidity also increases due to prolonged hospitalization and delay in initiating chemotherapy. Therefore prompt diagnosis and appropriate treatment is critical to improve prognosis. A 64-year-old man presented to the emergency department with severe abdominal pain. Chest X-ray showed free air below the right diaphragm. Abdominal CT scan also demonstrated free air in the peritoneal cavity with large wall defect in the lesser curvature of gastric lower body. Therefore, the patient underwent emergency operation and primary closure was done. Pathologic specimen obtained during surgery was compatible to diffuse large B cell lymphoma. Fifteen days after primary closure, the patient received subtotal gastrectomy and chemotherapy was initiated after recovery. Patient is currently being followed-up at outpatient department without any particular complications. Herein, we report a rare case of gastric lymphoma that initially presented as peritonitis because of spontaneous gastric perforation.

The Pleural Sandwich Sign in Two Cases of Primary Pleural Lymphoma

The sandwich sign is used to describe mesenteric lymphoma in which mesenteric vessels and fat are enveloped by enlarged mesenteric lymph nodes. We present two cases of primary pleural lymphoma demonstrating the "pleural sandwich sign". Contrast-enhanced computed tomography showed conglomerated parietal pleural and extrapleural masses encasing the intercostal arteries. Histopathological examinations confirmed low grade marginal zone B-cell lymphoma in an 80-year-old man and diffuse large B-cell lymphoma in a 68-year-old man. The pleural sandwich sign may suggest the diagnosis of primary pleural lymphoma.

CD20 Expression in Adult Patients with B-lineage Acute Lymphoblastic Leukemia and Its Prognostic Significance / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the relationship between the expression of CD20 antigen and clinical characteristics in adult patients with B-acute lymphoblastic leukemia(B-ALL).</p><p><b>METHODS</b>The CD20 expression of 126 acute lympho-blastic leukemia patients in our hospital from July 2009 to July 2012 were determined by flow cytometry. The characteristics, examination results and outcome were analyzed retrospectively. The complete remission rate (CR rate), relape rate, 2-year survival rate and 2-year event-free survival (EFS) of patients with CD20 positive and negative after the first cycle of chemstherapy were compared.</p><p><b>RESULTS</b>Positive rate of CD20 antigen expression in 126 patients was 24.4% (31 cases), negative rate of CD20 antigen expression in 126 patients was 75.6% (95 cases). No significant relationship was found between CD20 antigen expression and sex, age, peripheral blood leucocytes count and chromosomal changes. The relapse rate, 2-year survival rate (OS) and 2-year event-free survival (EFS) of adult patients with B-ALL in CD20 positive and negative groups were 53.3% and 38.0%, 52.1% and 92.3%, 33.7% and 70.8% respectively.</p><p><b>CONCLUSION</b>Expression of CD20 in adult patients with B-ALL did not related with clinical features, but related with poor prognosis.</p>