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CIC-rearranged sarcomas comprise a group of exceptionally aggressive round-cell sarcomas. These tumors most commonly demonstrate CIC::DUX4 fusion and show similar histopathology to Ewing sarcomas, though lesions mimicking vascular neoplasms have recently been described. Here, we describe a case of a patient with CIC::DUX4 fusion sarcoma identified using RNA-based molecular testing who was initially diagnosed with an endothelial neoplasm. The tumor showed extensive vasoformative growth, complete WT1 negativity, and global positive staining for ERG, CD31, and DUX4 by immunohistochemistry. Methylation testing of the tumor clustered more closely with angiosarcomas than with CIC-rearranged sarcomas. Our findings suggest that CIC::DUX4 fused neoplasms may demonstrate a more diverse phenotypic range than previously appreciated and offer evidence that both molecular and immunohistochemical studies are needed for accurate diagnosis.
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OBJECTIVES: This study reports analytical and clinical validation of a molecular signature response classifier (MSRC) that identifies rheumatoid arthritis (RA) patients who are non-responders to tumor necrosis factor-É inhibitors (TNFi). METHODS: The MSRC integrates patient-specific data from 19 gene expression features, anti-cyclic citrullinated protein serostatus, sex, body mass index, and patient global assessment into a single score. RESULTS: The MSRC results stratified samples (N = 174) according to non-response prediction with a positive predictive value of 87.7% (95% CI: 78-94%), sensitivity of 60.2% (95% CI: 50-69%), and specificity of 77.3% (95% CI: 65-87%). The 25-point scale was subdivided into three thresholds: signal not detected (<10.6), high (≥10.6), and very high (≥18.5). The MSRC relies on sequencing of RNA extracted from blood; this assay displays high gene expression concordance between inter- and intra-assay sample (R2 > 0.977) and minimal variation in cumulative gene assignment diversity, read mapping location, or gene-body coverage. The MSRC accuracy was 95.8% (46/48) for threshold concordance (no signal, high, very high). Intra- and inter-assay precision studies demonstrated high repeatability (92.6%, 25/27) and reproducibility (100%, 35/35). CONCLUSION: The MSRC is a robust assay that accurately and reproducibly detects an RA patient's molecular signature of non-response to TNFi therapies.
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Antirreumáticos , Artritis Reumatoide , Antirreumáticos/uso terapéutico , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Humanos , Valor Predictivo de las Pruebas , ARN , Reproducibilidad de los Resultados , Análisis de Secuencia de ARNRESUMEN
INTRODUCTION: Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. METHODS: The protein-protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. RESULTS: The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0-8.3, p value 0.0001). Odds ratios (3.4-8.8) were significant (p value < 0.01) for additional endpoints at 3 and 6 months, with AUC values up to 0.74. Among TNFi-exposed patients, the MSRC had an AUC of up to 0.83 and was associated with significant odds ratios of 3.3-26.6 by ACR, DAS28-CRP, and CDAI metrics. CONCLUSION: The MSRC stratifies patients according to likelihood of inadequate response to TNFi therapy and provides patient-specific data to guide therapy choice in RA for targeted therapy-naïve and TNFi-exposed patients.
A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists' confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.48.8 for targeted therapy-naïve patients and 3.326.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritisa heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients.
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Deleción Cromosómica , Eosinofilia/genética , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adulto , Cromosomas Humanos Par 7 , Eosinofilia/clasificación , Eosinofilia/patología , Reordenamiento Génico , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/patología , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Tirosina Quinasas/genética , Organización Mundial de la SaludRESUMEN
Myeloid neoplasms occasionally occur in patients with sickle cell disease, and the underlying connection between the two diseases is unclear. Herein, we retrospectively analyzed four cases of sickle cell disease patients who developed myeloid neoplasm. Age at time of diagnosis ranged from 27 to 59 years with a median of 35.5 years. Two patients were treated with hydroxyurea and the other two with supportive care alone, with one out of the four patients receiving additional treatment with hematopoietic stem cell transplant. Three patients presented with leukocytosis, and the remaining patient presented with pancytopenia. Two patients were diagnosed with myelodysplastic syndrome/myeloproliferative neoplasm, one with myelodysplastic syndrome, and the other with acute myeloid leukemia. All four cases demonstrated certain degrees of myelodysplasia and complex cytogenetic abnormalities with - 7/7q- and/or - 5/5q- or with 11q23 (KMT2A) rearrangement. This cytogenetic profile resembles that seen in therapy-related myeloid neoplasm, suggesting that myeloid neoplasm in the setting of sickle cell disease may represent a subcategory of the disease distinct from de novo myeloid neoplasm in general. Extensive literature review further demonstrates this similarity in cytogenetic profile, as well as in other associated pathologic features. Potential etiology includes therapy for sickle cell disease, disease-related immunomodulation, or disease-related chronic inflammation. We hypothesize that constant hematopoietic hyperplasia, stimulated by a hemolysis-induced cytokine storm, may increase the chance of somatic mutations/cytogenetic aberrations, resulting in transformation of myeloid precursors. This group of myeloid neoplasms seems to herald a dismal clinical outcome, with median survival <1 year, although the exact pathogenesis and biology of the disease remain to be investigated by large cohorts in future studies.
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Anemia de Células Falciformes/complicaciones , Leucemia Mieloide Aguda/complicaciones , Síndromes Mielodisplásicos/complicaciones , Adulto , Aberraciones Cromosómicas , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Estudios RetrospectivosRESUMEN
OBJECTIVES: Therapy-related chronic myeloid leukemia (CML) has been reported, but its clinical presentation and pathologic features have not yet been well characterized. METHODS: Twenty-one cases of CML following treatment for primary diseases were collected and retrospectively analyzed. RESULTS: The clinical presentation, pathologic features, and cytogenetic profile were similar to de novo CML. In particular, those with an isolated Philadelphia chromosome constituted 88.9% of our cases, and additional aberrations characteristic of therapy-related acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) were not identified in this study. The patients responded to imatinib/derivatives and survived with limited follow-up. CONCLUSIONS: Therapy-related CML has a clinical presentation, pathologic features, and cytogenetic profile akin to de novo CML. Absence of additional significant aberrations seems to suggest a pathogenesis different from therapy-related AML/MDS. Therapy-related CML exhibits a robust therapeutic response to imatinib/derivatives and favorable clinical outcomes similar to de novo CML.
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Composite lymphoma of T-/B-cell type is rare, and follicular lymphoma composite with peripheral T-cell lymphoma (PTCL) has not previously been reported. We report such a case with both neoplastic components displaying a unique zone of distribution. A 75-year-old male patient presented with generalized lymphadenopathy. Sections of axillary lymph node demonstrated potentially 2 clonal processes, PTCL with aberrant CD20 expression and follicular lymphoma. Interestingly, the 2 neoplastic components were confined to their respective classic distribution zones, with PTCL occupying the interfollicular areas and follicular lymphoma residing in follicles. Both populations were detected by flow cytometry, but their immunophenotypes were insufficient to define clonality. Nonetheless, biclonality was demonstrated by lymphoid receptor gene rearrangement analyses. Molecular cytogenetics showed IGH/BCL2 fusion in the follicular lymphoma and amplification of IGH gene or trisomy/tetrasomy 14 in the PTCL. The current case underscores the complexity of composite lymphoma and advocates a multimodal approach to establishing the diagnosis.