RESUMO
BACKGROUND: Diagnosing early-stage mycosis fungoides (MF) remains a significant challenge. The International Society for Cutaneous Lymphomas (ISCL) proposed an algorithm for diagnosing early MF incorporating clinical and histopathologic characteristics, as well as immunohistochemistry and molecular studies. Here we aim to examine the diagnostic utility of the ISCL algorithm. METHODS: In this single-center retrospective review, the ISCL algorithm was applied to 28 patients diagnosed with early-stage MF. Immunohistochemistry and molecular studies were not performed for all patients, so a subgroup analysis was conducted including 18 patients in whom both studies had been performed. We calculated the diagnostic sensitivity of the algorithm. Subsequently, we examined how modifying the algorithm's histopathologic criterion from epidermotropism without spongiosis to epidermotropism influenced its sensitivity. RESULTS: Forty-three percent (12/28) of the cohort and 50% (9/18) of the subgroup met the algorithm's diagnostic threshold. When the algorithm was modified, 71% of the cohort and 89% of the subgroup met the algorithm's threshold. CONCLUSION: While the ISCL algorithm is useful in diagnosing early-stage MF, its sensitivity remains suboptimal. Further refinement of the algorithm to capture spongiotic subtypes of MF may improve its diagnostic value.
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Micose Fungoide , Neoplasias Cutâneas , Algoritmos , Humanos , Imuno-Histoquímica , Micose Fungoide/diagnóstico , Micose Fungoide/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Topical corticosteroids alone or in combination with other therapies are widely used to treat mycosis fungoides (MF), but data on response rates to their use as monotherapy in MF are limited. OBJECTIVE: To evaluate the efficacy of topical corticosteroid monotherapy in MF; compare sex, age, stage distributions, and histopathologic features between responders and nonresponders. METHODS: A retrospective cross-sectional review of patients with MF from 2013 to 2019 treated at Thomas Jefferson University was conducted. Patients with biopsy-proven MF, all stages, who received topical corticosteroid monotherapy were included. Response rates were determined by percent change in body surface area (BSA) involvement and modified Severity-Weighted Assessment Tool (mSWAT). RESULTS: Of the 163 patients with MF in our database, 23% (37/163) initially received topical steroid monotherapy. Of these, 73% (27/37) improved, with an average 65% decrease in BSA (67% in mSWAT); 27% (10/37) did not respond/progressed, with an average 51.6% increase in BSA (57% in mSWAT); and 33% (12/37) had a complete response (BSA, 0%) with prolonged topical steroid use. Early-stage MF and female sex were more represented in responders. LIMITATIONS: Single-center retrospective design. CONCLUSIONS: Topical steroid monotherapy in early-stage MF can produce measurable improvements in BSA and mSWAT scores and achieve complete remission in a limited subset of patients.
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Glucocorticoides/administração & dosagem , Micose Fungoide/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/diagnóstico , Micose Fungoide/patologia , Estadiamento de Neoplasias , Indução de Remissão/métodos , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a World Health Organization (WHO)-defined diagnostic category within the highly heterogeneous group of mature post-thymic T-cell neoplasms. It is the most common subtype of mature post-thymic T-cell neoplasms globally, accounting for up to 35% of PTCL cases in Europe and North America. PTCL-NOS is a diagnosis of exclusion, comprising several disease entities that differ in biology, clinical presentation, and outcome. The diagnosis of PTCL-NOS is made based on the presence of typical histopathological features of lymphoma, an aberrant T-cell immunophenotype, often with a loss of CD5 and CD7, and a clonal T-cell receptor (TCR) gene rearrangement, in the appropriate clinical context. Unlike other types of T-cell lymphoma, recurrent mutations to assist with the diagnosis have not been identified. Patients often present with advanced stage. Prognosis is poor, with a 5-year overall survival (OS) of 20-30%. Anthracycline-based combination chemotherapy remains the most frequently used frontline strategy, with overall response rates (ORR) of 50-60%, and complete response rates (CRR) of 20-30%. Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) results in progression-free survivals (PFS) that compare favorably with historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking. Over the past decade, therapeutic agents approved in the relapsed and refractory setting have produced response rates of up to 33% and median PFS up to 18 months. Overall, outcomes remain poor and there is a dire need for more effective treatments. This review discusses the latest information on the diagnosis and treatment of PTCL-NOS.
Assuntos
Linfoma de Células T Periférico , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) can suppress and enhance immune functions. MSCs show promise as off-the-shelf cellular therapy for several disorders, including inflammation. OBJECTIVE: We investigated the effects of MSCs on the proliferation of PBMCs to allergic subjects (dust mite [DM]), allergic asthmatic subjects, or both. METHODS: Proliferation was studied by using tritiated thymidine uptake with or without MSCs. The refractoriness of PBMCs to DM was examined after preconditioning with MSCs and after repeated challenge with low-dose DM. Flow cytometry was used to study regulatory T cells and dendritic cells (DCs), and ELISA was used to study cytokine production. RESULTS: Seven subjects with allergic asthma met the inclusion/exclusion criteria. MSCs significantly (P < .05) reduced the proliferation of 6 subjects with allergic asthma but not those with allergy alone. The effect was specific to the allergen because MSCs did not affect challenges to tetanus toxoid. There was no change in CD4/CD25/forkhead box protein 3-positive cells, although there were decreased IFN-γ and increased IL-10 levels. Numbers of mature DCs were increased 6-fold. Refractoriness to DM was achieved by means of repeated exposure to low-dose DM and MSCs and also MSC- preconditioned MSC. CONCLUSION: MSCs suppressed the proliferation of DM-challenged PBMCs from allergic asthmatic subjects but not from allergic subjects without asthma. MSCs blunted the maturation of DCs but not regulatory T cells. Repeated exposure to low-dose DM and MSCs, as well as preconditioning of PBMCs with MSCs, caused refractoriness to DM. These findings have implications for the use of MSCs in attenuation of the inflammatory responses to allergic triggers in asthmatic patients with off-the-shelf MSCs.
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Alérgenos/imunologia , Asma/imunologia , Tolerância Imunológica/imunologia , Células-Tronco Mesenquimais/imunologia , Pyroglyphidae/imunologia , Adulto , Animais , Asma/metabolismo , Proliferação de Células , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Hipersensibilidade/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto JovemRESUMO
Treatment-specific responses and comprehensive disease characteristics are limited in black patients with cutaneous T-cell lymphoma (CTCL). These shortcomings prompted us to perform a subgroup analysis of black patients enrolled in the MAVORIC trial - an international, randomized, phase 3 trial comparing mogamulizumab vs. vorinostat in relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). Ten percent (N = 37) of the entire MAVORIC population (N = 372) identified as black. Significant clinical differences in black patients when compared to non-black patients included a younger median age at enrollment (53 vs. 66 years; p < 0.001), an increased frequency of MF as opposed to SS (73% vs. 52.8%; p < 0.001), and higher rates of earlier-stage disease (IB-IIA) at enrollment (37.8% vs. 21.2%; p = 0.022). Mogamulizumab offered similar response rates and progression-free survival in black patients (7.57 months) compared to the entire MAVORIC population (7.7 months) and was associated with a similar safety profile.
Assuntos
Micose Fungoide , Síndrome de Sézary , Neoplasias Cutâneas , Negro ou Afro-Americano , Humanos , Micose Fungoide/diagnóstico , Micose Fungoide/tratamento farmacológico , Recidiva Local de Neoplasia , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
T-cell PTLDs are lymphoid proliferations that develop in recipients of SOT or allogeneic HSCT. They carry an extremely poor prognosis with a reported median survival of only 6 months. The infrequency with which they are encountered makes treatment a challenge due to the lack of prospective trials to guide management. The significantly higher risk of morbidity and mortality in T-cell PTLD, compared to B-cell PTLD, underscores the challenge of treating these patients and the need for new therapeutic options. Brentuximab vedotin, an ADC targeting CD30, is FDA-approved in combination with CHP as front-line treatment for patients with CD30 expressing PTCL. Herein we report a case of CD30-positive T-cell PTLD that was successfully treated with BV-CHP, suggesting the added value of the addition of BV to chemotherapy, contributing to our patient's long and ongoing progression-free survival. To our knowledge, this is the first documented case of successful treatment using BV-CHP for a CD30-positive, EBV-negative, late T-cell PTLD.
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Linfoma de Células T Periférico , Transtornos Linfoproliferativos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Antígeno Ki-1/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/etiologia , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/etiologia , Prednisona/uso terapêuticoRESUMO
BACKGROUND: Questionnaire tools are increasingly being used to assess health related quality of life (HRQOL) in mycosis fungoides (MF) patients. However, a thorough understanding of the factors that lead to poor HRQoL in early stage disease and their distribution across patient subgroups is lacking. OBJECTIVES: To characterize factors affecting HRQoL as assessed by Skindex-29 in subgroups of patients with early stage MF seen at a multidisciplinary cutaneous lymphoma clinic. METHODS: Skindex-29, a multidimensional survey that evaluates HRQoL (emotions, symptoms, function), was distributed to early stage MF patients. Overall and component scores were analyzed in three groups: no evidence of disease (NED), active disease with limited early stage (AD-T1), and active disease with more extensive early stage (AD-T2). Scores were also compared among patients receiving different treatment modalities. RESULTS: 56 patients (9 NED, 36 AD-T1, and 11 AD-T2) were enrolled in the study. Overall Skindex-29 scores and scores for individual dimensions were comparable among the three sub-groups. Similarly, these scores did not significantly differ among treatment groups or after removal of patients with previous staging higher than IB. Analysis of individual questions revealed that NED patients reported higher scores for questions pertaining to anger and fatigue. CONCLUSIONS: Early stage MF patients enrolled in this study had high overall Skindex-29 scores. Surprisingly, Skindex-29 scores of NED patients were comparable to those of patients with active disease, T1 and T2, mostly due to anger and fatigue. Even when skin involvement is minimal or absent, MF patients continue to report impaired HRQoL.
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Ira , Fadiga/diagnóstico , Micose Fungoide/diagnóstico , Qualidade de Vida , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Progressão da Doença , Fadiga/etiologia , Fadiga/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/complicações , Micose Fungoide/psicologia , Micose Fungoide/terapia , Estadiamento de Neoplasias , Prognóstico , Pele/patologia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/psicologia , Neoplasias Cutâneas/terapia , Inquéritos e Questionários , Adulto JovemRESUMO
Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous and relatively rare family of extranodal non-Hodgkin's lymphomas (NHL) that are primarily localized to the skin. Most patients present with cutaneous patches, plaques, tumors, more rarely with erythroderma. The type of skin lesions and the surface extent of skin involvement, as well as the presence of extracutaneous disease, are the most important prognostic factors in patients with CTCL. Patients with early-stage disease can be effectively treated with skin-directed therapies only. As the disease progresses, systemic therapy often becomes necessary. In this review, we will provide an overview of the systemic treatment options for CTCL, including mechanism of action, efficacy, side effects, and discuss current principles for rational combination therapy and sequential use. Systemic therapy strategies have been evolving with the recent FDA approval of new monoclonal antibodies such as brentuximab vedotin and mogamulizumab to established drugs, such as retinoids, interferons (IFNs), and HDAC inhibitors. Numerous new agents are currently being studied in clinical trials. Identifying the genetic, molecular, and immunologic features of CTCL that are associated with disease progression, drug-resistance, and immune impairment, will optimize the utilization of existing therapies, and facilitate the development of new ones.
Assuntos
Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/terapia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/terapia , Humanos , Linfoma Cutâneo de Células T/patologia , Neoplasias Cutâneas/patologiaRESUMO
Mycosis fungoides (MF) and Sézary syndrome (SS) are two well-characterized skin limited and leukemic subtypes of cutaneous T-cell lymphoma (CTCL), respectively. Progressive global immune dysfunction and a multitude of specific immunological abnormalities have long been recognized as features of MF and SS. Therefore, a variety of immune-based therapies have been explored and used in the clinic for decades in the attempt to restore the immune imbalance in these malignancies. With recent advances in the development of novel immunotherapies in cancer treatment, new treatment modalities have emerged to complement the existing repertoire. Herein, we provide a comprehensive review of immune evasive mechanisms in MF/SS and summarize the established and emerging immunotherapies for these malignancies. We explain the underlying mechanisms of these immune-based therapies and derive recommendation from results of major clinical trials.
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Imunoterapia/métodos , Micose Fungoide/imunologia , Síndrome de Sézary/imunologia , Humanos , Micose Fungoide/patologia , Síndrome de Sézary/patologiaRESUMO
Mycosis fungoides and Sézary syndrome encompass over 70% of all cases of cutaneous T-cell lymphoma (CTCL). While early stage disease has excellent long-term survival rates, advanced stage disease (IIB-IV) carries a poor prognosis with a median 5-year overall survival rate of approximately 50%. Early stage and advanced stage disease have different treatment algorithms with systemic therapy being indicated upfront in the later. The role of allogeneic hematopoietic stem cell transplant (HSCT) has gained considerable interest in recent years as a treatment option for CTCL given the increasingly promising long-term outcomes in an otherwise incurable disease. Herein, we provide a brief update on the current advances in HSCT followed by a concise review of the role of HSCT for CTCL. We conclude with our recommendations to approaching HSCT as a curative treatment option for CTCL.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Micose Fungoide/terapia , Síndrome de Sézary/terapia , Condicionamento Pré-Transplante/métodos , Feminino , Humanos , Masculino , Micose Fungoide/patologia , Síndrome de Sézary/patologia , Transplante HomólogoRESUMO
Mycosis fungoides is the most common form of cutaneous T cell lymphoma. Although normally presenting to physicians at an early stage and with an indolent course, mycosis fungoides can have a varied presentation. The National Comprehensive Cancer Network (NCCN) has created guidelines for the treatment and staging of mycosis fungoides. Although comprehensive, in practice these guidelines do not provide specific treatment regimens for lesions located in difficult locations and those recalcitrant to the recommended therapy. Because of this, suggestions based on the practices and decisions made at the multidisciplinary cutaneous lymphoma clinic at the Sidney Kimmel Cancer Center at Thomas Jefferson University, Philadelphia, PA, USA, are presented here. Lesions located in areas such as the face and intertriginous zones are often challenging to treat because first-line therapies are often inappropriate, with the locations increasing the possibility of side effects. Additionally, lesions located in the bathing suit distribution are often nonresponsive to first-line therapies for reasons still undetermined. Finally, although well-described, erythroderma secondary to mycosis fungoides is challenging to treat, with controversy surrounding various methods of control. This article both highlights difficult clinical scenarios and reviews the recommended treatment as provided by the NCCN guidelines and provides alternative therapy for lesions that are either difficult to treat because of the location or are recalcitrant to the recommended therapy. With suggestions for the apparent gaps in guidelines, providers can better treat patients who present with more complicated conditions.
Assuntos
Dermatite Esfoliativa/terapia , Micose Fungoide/terapia , Neoplasias Cutâneas/terapia , Adulto , Antineoplásicos/administração & dosagem , Biópsia , Nádegas , Terapia Combinada/métodos , Dermatite Esfoliativa/etiologia , Fármacos Dermatológicos/administração & dosagem , Dermatologia/normas , Fracionamento da Dose de Radiação , Face , Feminino , Humanos , Masculino , Oncologia/normas , Pessoa de Meia-Idade , Micose Fungoide/complicações , Micose Fungoide/patologia , Guias de Prática Clínica como Assunto , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Terapia Ultravioleta/métodosRESUMO
Primary cutaneous CD30+ T cell lymphoproliferative disorders (pcCD30+ T cell LPDs) are a spectrum of pre-malignant to frankly neoplastic lymphoproliferations that comprise lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline lesions. Although the atypical T cells that are the hallmark of these disorders share the expression of CD30, as the identifying marker, the clinical presentation, histological features and clinical course are vastly different. Furthermore, histopathologic features of pcCD30+ T cell LPDs may overlap with other cutaneous and systemic lymphomas. While most pcCD30+ T cell LPDs have an excellent prognosis, systemic lymphomas typically have a poorer outcome. CD30 has now been shown to be a reliable therapeutic target in pcCD30+ T cell LPDs. This review will emphasize the structure and function of CD30, along with the clinical and pathological spectrum of pcCD30+ T cell LPDs. It will also highlight other CD30+ lymphoproliferations that must be differentiated by careful clinical and pathological correlation.
Assuntos
Antígeno Ki-1/metabolismo , Linfoma Cutâneo de Células T/genética , Transtornos Linfoproliferativos/genética , Pele/patologia , Humanos , Linfoma Cutâneo de Células T/patologia , Transtornos Linfoproliferativos/patologia , Prognóstico , Neoplasias Cutâneas/patologiaRESUMO
Angioimmunoblastic T-cell lymphoma (AITL) is one of four major subtypes of nodal peripheral T cell lymphoma, characterized by its cell of origin, the follicular helper T-cell (TFH). Patients typically present with prominent constitutional (B) symptoms, generalized lymphadenopathy, hepatosplenomegaly, cytopenias, and rash. Here we present a case of a 62-year-old male with progressive cervical adenopathy, fevers and weight loss presenting with extreme polyclonal plasmacytosis and high plasma EBV viral load. While the initial presentation appeared to mimic plasma cell leukemia or severe infection, lymph node biopsy and bone marrow biopsy confirmed a diagnosis of AITL. This case highlights the heterogeneity of the clinical presentation of AITL to enable physicians to more promptly recognize, diagnose and initiate treatment.
RESUMO
Autoimmune paraneoplastic and neoplasm-associated skin syndromes are characterized by autoimmune-mediated cutaneous lesions in the presence of a neoplasm. The identification of these syndromes provides information about the underlying tumor, systemic symptoms, and debilitating complications. The recognition of these syndromes is particularly helpful in cases of skin lesions presenting as the first sign of the malignancy, and the underlying malignancy can be treated in a timely manner. Autoimmune paraneoplastic and neoplasm-associated bullous skin syndromes are characterized by blister formation due to an autoimmune response to components of the epidermis or basement membrane in the context of a neoplasm. The clinical manifestations, histopathology and immunopathology findings, target antigens, associated neoplasm, current diagnostic criteria, current understanding of pathogenesis, and treatment options for a selection of four diseases are reviewed. Paraneoplastic pemphigus manifests with clinically distinct painful mucosal erosions and polymorphic cutaneous lesions, and is often associated with lymphoproliferative neoplasm. In contrast, bullous pemphigoid associated with neoplasm presents with large tense subepidermal bullae of the skin, and mild mucosal involvement, but without unique clinical features. Mucous membrane pemphigoid associated with neoplasm is a disorder of chronic subepithelial blisters that evolve into erosions and ulcerations that heal with scarring, and involves stratified squamous mucosal surfaces. Linear IgA dermatosis associated with neoplasm is characterized by annularly grouped pruritic papules, vesicles, and bullae along the extensor surfaces of elbows, knees, and buttocks. Physicians should be aware that these autoimmune paraneoplastic and neoplasm-associated syndromes can manifest distinct or similar clinical features as compared with the non-neoplastic counterparts.
Assuntos
Neoplasias/complicações , Síndromes Paraneoplásicas/etiologia , Pênfigo/etiologia , Dermatopatias Vesiculobolhosas/etiologia , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Doenças Autoimunes/patologia , Humanos , Mucosa/patologia , Neoplasias/diagnóstico , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/patologia , Penfigoide Bolhoso/diagnóstico , Penfigoide Bolhoso/etiologia , Penfigoide Bolhoso/patologia , Pênfigo/diagnóstico , Pênfigo/patologia , Dermatopatias Vesiculobolhosas/diagnóstico , Dermatopatias Vesiculobolhosas/patologiaRESUMO
Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To examine this effect in a clinical setting, 14 schizophrenic and bipolar patients were treated with valproic acid (Depakote ER), either as monotherapy or in combination with antipsychotics, over a period of 4 weeks. AcH3 and acH4 levels from lymphocyte nuclear protein extracts were measured by Western Blot. Treatment with Depakote ER resulted in a significant increase of acH3 and a trend-level increase of acH4. Levels of valproic acid were positively and significantly correlated with percent increase in acH3 but not acH4. Schizophrenia patients were significantly less likely to increase their acH3 and acH4 levels after 4 weeks on Depakote ER. The authors consider these results in the context of future application of HDAC inhibitors to the treatment of psychiatric disorders.
Assuntos
Antipsicóticos/uso terapêutico , Montagem e Desmontagem da Cromatina/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Ácido Valproico/uso terapêutico , Adulto , Western Blotting , Manual Diagnóstico e Estatístico de Transtornos Mentais , Histona Acetiltransferases/metabolismo , Humanos , Pessoa de Meia-Idade , Vigilância da População/métodosRESUMO
Chronic hepatitis C virus (HCV) infection is a complex, multi-organ disorder, not just limited to the liver. Mixed cryoglobulinemia (MC) type 2 is a common extrahepatic complication, in which immunoglobulin complexes deposit in vascular endothelium. This in turn creates a diffuse inflammatory reaction, leading to a variety of disorders involving multiple systems. We report the rare case of a patient with cryoglobulinemia, cutaneous vasculitis, membroproliferative glomerulonephritis, and B cell lymphoma with a variant t(6;10) translocation in the setting of an untreated, chronic HCV infection. This case highlights the challenge associated with diagnosing and managing such a complex presentation.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Crioglobulinemia/etiologia , Glomerulonefrite Membranoproliferativa/etiologia , Hepatite C Crônica/complicações , Linfoma de Células B/etiologia , Vasculite/etiologia , Anticorpos Monoclonais Murinos/uso terapêutico , Crioglobulinemia/diagnóstico , Crioglobulinemia/tratamento farmacológico , Diagnóstico Diferencial , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Hepacivirus , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/tratamento farmacológico , Masculino , Hemissuccinato de Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Rituximab , Translocação Genética , Vasculite/diagnóstico , Vasculite/tratamento farmacológicoRESUMO
Mesenchymal stem cells (MSCs) are promising cellular suppressor of inflammation. This function of MSCs is partly due to their licensing by inflammatory mediators. In cases with reduced inflammation, MSCs could become immune-enhancer cells. MSCs can suppress the inflammatory response of antigen-challenged lymphocytes from allergic asthma. Although allergic rhinitis (AR) is also an inflammatory response, it is unclear if MSCs can exert similar suppression. This study investigated the immune effects (suppressor vs enhancer) of MSCs on allergen-stimulated lymphocytes from AR subjects (grass or weed allergy). In contrast to subjects with allergic asthma, MSCs caused a significant (P<0.05) increase in the proliferation of antigen-challenged lymphocytes from AR subjects. The increase in lymphocyte proliferation was caused by the MSCs presenting the allergens to CD4(+) T cells (antigen-presenting cells (APCs)). This correlated with increased production of inflammatory cytokines from T cells, and increased expressions of major histocompatibility complex (MHC)-II and CD86 on MSCs. The specificity of APC function was demonstrated in APC assay using MSCs that were knocked down for the master regulator of MHC-II transcription, CIITA. The difference in the effects of MSCs on allergic asthma and AR could not be explained by the sensitivity to the allergen, based on skin tests. Thus, we deduced that the contrasting immune effects of MSCs for antigen-challenged lymphocytes on AR and allergic asthma could be disease specific. It is possible that the enhanced inflammation from asthma might be required to license the MSCs to become suppressor cells. This study underscores the need for robust preclinical studies to effectively translate MSCs for any inflammatory disorder.
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OBJECTIVE: The emerging field of psychiatric epigenetics is constrained by the dearth of research methods feasible in living patients. With this focus, we report on two separate approaches, one in vitro and one in vivo, developed in our laboratory. METHOD: In the first approach, we isolated lymphocytes from 12 subjects and cultured their cells with either 0.7 mM valproic acid (VPA), 100 nM Trichostatin A (TSA), or DMSO (control) for 24h based upon previous dose response experiments. We then measured GAD67 mRNA expression using realtime RT-PCR, total acetylated histone 3 (H3K9,K14ac) levels using Western blot analysis, and attachment of H3K9,K14ac to the GAD67 promoter using ChIP. In the second approach, we measured GAD67 mRNA and total H3K9,K14ac levels in lymphocytes from 11 schizophrenia and 7 bipolar patients before and after 4 weeks of clinical treatment with Depakote ER (VPA). RESULTS: In the first approach, VPA induced a 383% increase in GAD67 mRNA, an 89% increase in total H3K9,K14ac levels, and a 482% increase in H3K9,K14ac attachment to the GAD67 promoter. TSA induced comparable changes on all measures. In the second approach, bipolar subjects had significantly higher baseline levels of H3K9,K14ac compared to subjects with schizophrenia. Subjects with clinically relevant serum levels of VPA (> or = 65 microg/mL) showed a significant increase in GAD67 mRNA expression. CONCLUSIONS: Our results utilizing two separate approaches for examining chromatin remodeling in real clinical time provide possible means to investigate epigenetic events in living patients.