RESUMO
PURPOSE: Analyzing bone marrow in the hematologic cancer myelofibrosis requires endpoint histology in mouse models and bone marrow biopsies in patients. These methods hinder the ability to monitor therapy over time. Preclinical studies typically begin treatment before mice develop myelofibrosis, unlike patients who begin therapy only after onset of disease. Using clinically relevant, quantitative MRI metrics allowed us to evaluate treatment in mice with established myelofibrosis. METHODS: We used chemical shift-encoded fat imaging, DWI, and magnetization transfer sequences to quantify bone marrow fat, cellularity, and macromolecular components in a mouse model of myelofibrosis. We monitored spleen volume, the established imaging marker for treatment, with anatomic MRI. After confirming bone marrow disease by MRI, we randomized mice to treatment with an approved drug (ruxolitinib or fedratinib) or an investigational agent, navitoclax, for 33 days. We measured the effects of therapy over time with bone marrow and spleen MRI. RESULTS: All treatments produced heterogeneous responses with improvements in bone marrow evident in subsets of individual mice in all treatment groups. Reductions in spleen volume commonly occurred without corresponding improvement in bone marrow. MRI revealed patterns associated with effective and ineffective responses to treatment in bone marrow and identified regional variations in efficacy within a bone. CONCLUSIONS: Quantitative MRI revealed modest, heterogeneous improvements in bone marrow disease when treating mice with established myelofibrosis. These results emphasize the value of bone marrow MRI to assess treatment in preclinical models and the potential to advance clinical trials for patients.
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Medula Óssea , Mielofibrose Primária , Animais , Camundongos , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Imageamento por Ressonância Magnética , Mielofibrose Primária/diagnóstico por imagem , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Baço/diagnóstico por imagemRESUMO
Histopathology, the standard method to assess BM in hematologic malignancies such as myeloproliferative neoplasms (MPNs), suffers from notable limitations in both research and clinical settings. BM biopsies in patients fail to detect disease heterogeneity, may yield a nondiagnostic sample, and cannot be repeated frequently in clinical oncology. Endpoint histopathology precludes monitoring disease progression and response to therapy in the same mouse over time, missing likely variations among mice. To overcome these shortcomings, we used MRI to measure changes in cellularity, macromolecular constituents, and fat versus hematopoietic cells in BM using diffusion-weighted imaging (DWI), magnetization transfer, and chemical shift-encoded fat imaging. Combining metrics from these imaging parameters revealed dynamic alterations in BM following myeloablative radiation and transplantation. In a mouse MPLW515L BM transplant model of MPN, MRI detected effects of a JAK2 inhibitor, ruxolitinib, within 5 days of initiating treatment and identified differing kinetics of treatment responses in subregions of the tibia. Histopathology validated the MRI results for BM composition and heterogeneity. Anatomic MRI scans also showed reductions in spleen volume during treatment. These findings establish an innovative, clinically translatable MRI approach to quantify spatial and temporal changes in BM in MPN.
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Neoplasias Hematológicas , Imageamento por Ressonância Magnética Multiparamétrica , Transtornos Mieloproliferativos , Animais , Imageamento por Ressonância Magnética , Camundongos , Transtornos Mieloproliferativos/diagnóstico por imagemRESUMO
Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications.
Assuntos
Antineoplásicos , Mielofibrose Primária , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML-CK). In this study, we uncover three different modes of ERG amplification in AML-CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high-risk B-lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low-grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.
Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Cariótipo Anormal , Aberrações Cromossômicas , Humanos , Cariótipo , Leucemia Mieloide Aguda/patologia , Masculino , Mutação , Regulador Transcricional ERG/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Acute leukemia with mixed-phenotype blasts is associated with poor outcomes. There are no standard treatment regimens. Due to disease heterogeneity, controversy exists over whether an AML-based, ALL-based, or a combined (hybrid) AML/ALL-based regimen is most appropriate. MATERIALS AND METHODS: We conducted a single-center, retrospective case series review of patients with acute leukemia with mixed phenotype blasts as described by the European Group for Immunological Characterization of Leukemia (EGIL) or the 2008 WHO classification. Patients were treated from November 2014 and December 2019 with the combination chemotherapy regimen FLAG-idarubicin-vincristine-prednisone with or without rituximab. Outcomes included induction response, time to transplant, time to relapse, overall survival, time to neutrophil or platelet recovery, infection, and duration of hospitalization. RESULTS: The median age was 68 years (range 21-77). Six patients (87.5 %) had unfavorable/complex cytogenetics. All patients achieved a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). Estimated 1-year overall survival was 85.7 %. There were no deaths during induction, with a 22 day median duration of hospitalization for induction. CONCLUSION: The combination of FLAG, idarubicin, vincristine, and prednisone (FLAG-VIPR) demonstrated favorable induction responses in a disease state with historically poor outcomes and should be studied in a prospective clinical trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda , Prednisona/administração & dosagem , Vidarabina/análogos & derivados , Vincristina/administração & dosagem , Adulto , Idoso , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagemRESUMO
Advances in digital pathology have allowed a number of opportunities such as decision support using artificial intelligence (AI). The application of AI to digital pathology data shows promise as an aid for pathologists in the diagnosis of haematological disorders. AI-based applications have embraced benign haematology, diagnosing leukaemia and lymphoma, as well as ancillary testing modalities including flow cytometry. In this review, we highlight the progress made to date in machine learning applications in haematopathology, summarise important studies in this field, and highlight key limitations. We further present our outlook on the future direction and trends for AI to support diagnostic decisions in haematopathology.
Assuntos
Hematologia , Leucemia/diagnóstico , Linfoma/diagnóstico , Aprendizado de Máquina , Inteligência Artificial , Citometria de Fluxo , Humanos , Leucemia/patologia , Linfoma/patologiaRESUMO
Fine needle aspiration (FNA) has become increasingly popular in the evaluation of lymph nodes for lymphoproliferative disorders, but there are limitations to accurate subclassification of lymphoma using morphology alone. This case aims to expand diagnostic considerations of large B-cell populations identified on FNA material. We also address the significance of Epstein-Barr virus (EBV) DNA in the workup of patients with suspected lymphoma by FNA.
Assuntos
Linfócitos B/patologia , Linfonodos/patologia , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Idoso , Biópsia por Agulha Fina/métodos , Citodiagnóstico/métodos , Humanos , MasculinoRESUMO
The diagnosis of pure erythroid leukemia (PEL) can be challenging. Prompt identification of CD45+, CD34-, CD71+, CD117+, and E-cadherin+ erythroblasts is important. The differential diagnosis is broad and includes megaloblastic anemia.
RESUMO
Notch signaling regulates squamous cell proliferation and differentiation and is frequently disrupted in squamous cell carcinomas, in which Notch is tumor suppressive. Here, we show that conditional activation of Notch in squamous cells activates a context-specific gene expression program through lineage-specific regulatory elements. Among direct Notch target genes are multiple DNA damage response genes, including IER5, which we show is required for Notch-induced differentiation of squamous carcinoma cells and TERT-immortalized keratinocytes. IER5 is epistatic to PPP2R2A, a gene that encodes the PP2A B55α subunit, which we show interacts with IER5 in cells and in purified systems. Thus, Notch and DNA-damage response pathways converge in squamous cells on common genes that promote differentiation, which may serve to eliminate damaged cells from the proliferative pool. We further propose that crosstalk involving Notch and PP2A enables tuning and integration of Notch signaling with other pathways that regulate squamous differentiation.
Assuntos
Diferenciação Celular/genética , Células Epiteliais/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas Nucleares/metabolismo , Receptores Notch/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Dano ao DNA/genética , Humanos , Proteínas Imediatamente Precoces/genética , Queratinócitos/metabolismo , Proteínas Nucleares/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores Notch/genética , Transdução de Sinais/genéticaRESUMO
We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome-like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.
Assuntos
Janus Quinase 2/genética , Leucemia/diagnóstico , Leucemia/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Fusão Oncogênica/genética , Fenótipo , Fatores de Transcrição/genética , Adulto , Biópsia , Medula Óssea/patologia , Terapia Combinada , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia/terapia , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , TerapêuticaRESUMO
The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.
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Leucemia Aguda Bifenotípica , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Adulto , Tratamento Farmacológico/métodos , Feminino , Genômica , Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Leucemia Aguda Bifenotípica/genética , Leucemia Aguda Bifenotípica/terapia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.
Assuntos
Anemia de Diamond-Blackfan/patologia , Ribossomos/metabolismo , Regiões 5' não Traduzidas , Anemia de Diamond-Blackfan/genética , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Células da Medula Óssea/metabolismo , Células Cultivadas , Feminino , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Mutação de Sentido Incorreto , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Ribossômicas/antagonistas & inibidores , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Ribossomos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVES: Myeloid proliferative disorders associated with Down syndrome (MPD-DS), including transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome (DS), harbor mutations of GATA1, a transcription factor essential for erythroid and megakaryocytic development. These mutations result in a N-terminally truncated GATA1 (GATA1s) and prohibit the production of the full-length GATA1 (GATA1f). Here, we demonstrate the utility of immunohistochemical GATA1f reactivity in diagnosing MPD-DS. METHODS: Immunohistochemical studies for GATA1f expression were performed on bone marrow biopsy specimens. RESULTS: In all cases of MPD-DS, megakaryocytes lacked GATA1f expression. In contrast, GATA1f expression was detected in megakaryocytes in all specimen types from patients without DS (normal bone marrows, pediatric myelodysplastic syndrome, juvenile myelomonocytic leukemia, adult acute megakaryocytic leukemia [pediatric and adult; without trisomy 2]), as well as normal bone marrows from patients with DS. CONCLUSIONS: The lack of GATA1f expression is a sensitive and specific immunohistochemical marker for MPD-DS.
Assuntos
Síndrome de Down/diagnóstico , Fator de Transcrição GATA1/metabolismo , Reação Leucemoide/diagnóstico , Megacariócitos/metabolismo , Biomarcadores/metabolismo , Western Blotting , Síndrome de Down/metabolismo , Humanos , Imuno-Histoquímica , Reação Leucemoide/metabolismo , Sensibilidade e EspecificidadeRESUMO
Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 clinical response, suggesting a common efficacy signature between a targeted therapy and immunotherapy. When searching for genes related to lapatinib resistance, CARE identified PRKD3 as the top candidate. PRKD3 inhibition, by both small interfering RNA and compounds, significantly sensitized breast cancer cells to lapatinib. Thus, CARE should enable large-scale inference of response biomarkers and drug combinations for targeted therapies using compound screen data.
Assuntos
Biologia Computacional/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/genética , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Lapatinib/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Software , Transcriptoma/genética , Resultado do TratamentoRESUMO
Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel ß 1 (CNGB1) cause approximately 4% of autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers of progression in patients with RP are needed to assess therapeutic outcomes. Here, we evaluated RP patients with CNGB1 mutations for potential biomarkers of progression and compared human phenotypes with those of mouse and dog models of the disease. Additionally, we used gene augmentation therapy in a CNGß1-deficient dog model to evaluate potential translation to patients. CNGB1-deficient RP patients and mouse and dog models had a similar phenotype characterized by early loss of rod function and slow rod photoreceptor loss with a secondary decline in cone function. Advanced imaging showed promise for evaluating RP progression in human patients, and gene augmentation using adeno-associated virus vectors robustly sustained the rescue of rod function and preserved retinal structure in the dog model. Together, our results reveal an early loss of rod function in CNGB1-deficient patients and a wide window for therapeutic intervention. Moreover, the identification of potential biomarkers of outcome measures, availability of relevant animal models, and robust functional rescue from gene augmentation therapy support future work to move CNGB1-RP therapies toward clinical trials.
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Canais de Cátion Regulados por Nucleotídeos Cíclicos/deficiência , Mutação , Proteínas do Tecido Nervoso/deficiência , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Animais , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Dependovirus , Modelos Animais de Doenças , Cães , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Retinose Pigmentar/patologia , Retinose Pigmentar/terapia , Transdução GenéticaRESUMO
Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.
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Linfócitos B/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfoma de Células B/genética , Linfoma de Células B/patologia , Oncogenes , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Biópsia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Rearranjo Gênico , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Notch/genética , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Autoimmune retinopathy (AIR) is a rare but potentially blinding condition that is often underdiagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies. AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. The goal of this communication is to assess the effects of rituximab infusions on electroretinogram (ERG) responses and visual function outcomes in patients with non-paraneoplastic autoimmune retinopathy (npAIR). RESULTS: Following infusion(s), three out of five patients showed no evidence of disease progression or improved, while two patients continued to progress on ERG. One patient demonstrated improvement in visual acuity (2 lines) in both eyes. ERG responses provided objective monitoring of patients' visual function and response to immunosuppression over time. CONCLUSIONS: These findings suggest that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in our case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients' progression during treatment.
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Doenças Autoimunes/tratamento farmacológico , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/etiologia , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Peripapillary sparing is a characteristic that is traditionally described as pathognomonic for Stargardt disease. MATERIALS AND METHODS: We present a multimodal assessment of four Leber congenital amaurosis (LCA) cases with congenital macular atrophy and severely attenuated electroretinogram findings caused by bilallelic mutations in RDH12. RESULTS: Fundus autofluorescence imaging revealed a general loss of retinal pigment epithelium across the macula except for the peripapillary region in both eyes of all patients. Spectral domain-optical coherence tomography confirmed relative preservation in this area along with retinal thinning and excavation throughout the rest of the macula. LCA was diagnosed based on clinical exam and retinal imaging, and subsequently confirmed with genetic testing. CONCLUSIONS: Peripapillary sparing is a novel phenotypic feature of RDH12-associated LCA.
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Oxirredutases do Álcool/genética , Amaurose Congênita de Leber/genética , Mutação , Adolescente , Atrofia , Criança , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Testes Genéticos , Genótipo , Humanos , Amaurose Congênita de Leber/diagnóstico , Masculino , Imagem Multimodal , Disco Óptico/patologia , Linhagem , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica , Adulto JovemRESUMO
OBJECTIVES: GATA binding factor 1 (GATA1) is a transcription factor essential for erythromegakaryocytic differentiation. Given its function in lineage specification, we sought to evaluate the immunohistochemical profile of GATA1 in normal marrow and acute leukemia and assess the use of GATA1 as a specific erythromegakaryocytic immunohistochemical marker. METHODS: Immunohistochemical studies for GATA1 expression were performed on bone marrow biopsy specimens to define its role in the evaluation of acute leukemia and other hematologic disorders. RESULTS: In normal marrows, intense nuclear reactivity is seen in immature erythroid precursors and megakaryocytes. Weak to moderate nuclear positivity is seen in eosinophils and mast cells. In marrows involved by acute leukemia, blasts of pure erythroleukemia and acute megakaryoblastic leukemia exhibit intense nuclear GATA1 positivity, while blasts of acute myeloid leukemia of other categories are negative. GATA1 is also absent in the blasts of acute lymphoblastic leukemia/lymphoma and in the neoplastic cells of metastatic carcinoma and plasma cell neoplasms. CONCLUSIONS: Intense GATA1 nuclear expression is a sensitive and specific marker for cells of erythroid and megakaryocytic lineages and is an excellent marker for neoplastic cells of pure erythroleukemia and acute megakaryoblastic leukemia.
Assuntos
Fator de Transcrição GATA1/metabolismo , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Megacarioblástica Aguda/metabolismo , Medula Óssea/metabolismo , Medula Óssea/patologia , Diferenciação Celular , Núcleo Celular/metabolismo , Células Eritroides/metabolismo , Células Eritroides/patologia , Fator de Transcrição GATA1/genética , Marcadores Genéticos/genética , Humanos , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/patologia , Leucemia Megacarioblástica Aguda/diagnóstico , Leucemia Megacarioblástica Aguda/patologia , Megacariócitos/metabolismo , Megacariócitos/patologia , Sensibilidade e EspecificidadeRESUMO
Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. While human embryonic stem cells (ESCs) have provided the precedent for regenerative medicine, the development of induced pluripotent stem cells (iPSCs) revolutionized this field. iPSCs allow for the development of many types of retinal cells, including those of the retinal pigment epithelium, photoreceptors, and ganglion cells, and can model polygenic diseases such as age-related macular degeneration. Cellular programming and reprogramming technology is especially useful in retinal diseases, as it allows for the study of living cells that have genetic variants that are specific to patients' diseases. Since iPSCs are a self-renewing resource, scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Challenges in the use of stem cells are present from the scientific, ethical, and political realms. These include transplant complications leading to anatomically incorrect placement, concern for tumorigenesis, and incomplete targeting of differentiation leading to contamination by different types of cells. Despite these limitations, human ESCs and iPSCs specific to individual patients can revolutionize the study of retinal disease and may be effective therapies for conditions currently considered incurable.