Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell neoplasms encompass a heterogeneous group of relatively rare disease entities. This review, focused on lymphoblastic tumors (T-ALL/LBL) and nodal-based peripheral T-cell lymphomas (PTCL), summarizes recent advances in the molecular characterization of these diseases. In T-ALL/LBL, molecular subgroups delineated by gene expression profiling correlate with leukemic arrest at specific stages of normal thymocyte development and different oncogenic pathways, and seem to be of interest for prognosis prediction. Angioimmunoblastic T-cell lymphoma (AITL), one of the most common PTCL entities, comprises neoplastic cells with a molecular signature similar to normal follicular helper T cells, and this cellular derivation might account for several of the peculiar aspects of this disease. Except in ALK-positive anaplastic large cell lymphoma, defined by ALK gene fusions, chromosomal translocations are otherwise rare in PTCLs, but some recurrent rearrangements might be associated with distinct lymphoma subtypes. In PTCL, not otherwise specified (PTCL, NOS), novel molecular biomarkers of potential therapeutic interest have been recently identified.
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PMID:Molecular classification of T-cell lymphomas. 1923 83

Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.
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PMID:Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma. 2013 72

Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T-cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T-cell lymphoma (NKTCL) from the International Peripheral T-cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK(+) anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T-cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T-cell leukemia/lymphoma (ATLL), with a 2-year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK(-) ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK(+) ALCL, or enteropathy-associated T-cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL.
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PMID:The prognostic significance of lymphopenia in peripheral T-cell and natural killer/T-cell lymphomas: a study of 826 cases from the International Peripheral T-cell Lymphoma Project. 2248 78

The peripheral T-cell lymphomas represent about 15% to 20% of non-Hodgkin lymphomas and are marked by clinical and pathologic heterogeneity. The most common T-cell entities include peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative, which account for approximately 60% of T-cell lymphoma cases. Because of the rarity of T-cell lymphomas and lack of randomized prospective studies, treatment for these diseases is not well defined. Current treatment strategies draw from data from phase II studies, retrospective analyses, and personal experience. For fit patients who can tolerate treatment with curative intent, we treat peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma anaplastic lymphoma kinase-negative similarly with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based induction therapy followed by consolidation with autologous stem cell transplant. Given the marked differences in histology, biology, and clinical presentation for these diseases, it is likely that they should be approached differently. Furthermore, prognostic factors and degree of chemosensitivity as measured by FDG-PET (fluorodeoxyglucose positron emission tomography) should likely be used to guide patients along different treatment pathways. We have a long way to go toward perfecting the treatment for T-cell lymphoma. We believe that a uniform treatment approach for patients with aggressive T-cell lymphoma is not appropriate; however, we do not yet have enough data to support an individualized approach to treatment. Clinical and biologic prognostic factors, degree of chemosensitivity as measured by FDG-PET, and histology should all likely have a role in directing patients along different treatment pathways, but prospective studies are needed to confirm this.
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PMID:Should patients with aggressive peripheral T-cell lymphoma all be treated the same?: no... well yes, ...but maybe not for long. 2300 50

Except for ALK-positive anaplastic large cell lymphoma (ALCL) and patients with limited disease, mature T- and natural killer (NK) cell lymphomas are disorders with a poor prognosis. Patients with relapsed or refractory ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) after allogeneic transplantation of hematopoietic stem cells (alloSCT) achieve long-term survival in 35%-50% of cases. Survival in patients with less frequent subtypes (NK/T-cell lymphoma, cutaneous T-cell lymphomas, acute T-cell leukemia/lymphoma, or hepatosplenic T-cell lymphoma) also seems promising. These results are significantly better than those of any other treatment modality, including the new drugs. Therefore, alloSCT should be considered in patients with relapsed/ refractory T-cell lymphoma. Because of low patient numbers and lack of comparative studies, the optimum conditioning regimen prior to transplantation as well as other details of the transplant procedure remain unknown and await further study. Studies investigating the role of alloSCT as part of first-line therapy in poor-risk T-cell lymphomas are ongoing. At present, data are not sufficient to recommend alloSCT outside of clinical trials.
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PMID:Allogeneic transplantation in T-cell lymphomas. 2446 18

Peripheral T-cell lymphomas (PTCL) are rare neoplasms that in most instances respond poorly to conventional chemotherapies. Four varieties--PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK+ anaplastic T-cell lymphoma (ALCL), and ALK- ALCL--account for about 60 % of them. Their classification is difficult because of the wide spectrum of morphologic features and the lack of robust immunohistochemical markers. Thus, high-throughput technologies can importantly contribute to their better understanding. In particular, gene expression profiling has cleared the borders among PTCL/NOS, ALK- ALCL and AITL. In fact, gene signatures have been developed even from formalin-fixed paraffin-embedded tissue samples that definitely distinguish one tumor from the other(s). This has important practical implications: for instance on routine diagnostics PTCL/NOS expressing CD30 can be easily confused with ALK- ALCL, but has a much worse prognosis. Therefore, the clear-cut distinction between the two conditions is pivotal to understand the results of ongoing trials with Brentuximab Vedotin, targeting the CD30 molecule. Besides improving the diagnosis, molecular studies have provided the rationale for the usage of novel drugs in the setting of PTCLs, such as ALK inhibitors in ALK+ ALCL, anti-angiogenetic drugs in AITL, and tyrosine kinase inhibitors in PTCL/NOS and ALK+ and ALK- ALCLs.
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PMID:Molecular genetics of peripheral T-cell lymphomas. 2450 39

The peripheral T-cell lymphomas (PTCLs) encompass a heterogeneous group of diseases that have generally been associated with poor prognosis. The most common PTCLs, peripheral T-cell lymphoma, not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALK-negative), despite their unique presentations and histologies, are currently treated similarly. Here we discuss our general approach to the treatment of the most common PTCLs. Based on the best data currently available, which include retrospective analyses and phase 2 prospective studies, our approach has involved cyclophosphamide, doxorubicin, vincristine, prednisone-based therapy followed by consolidation in first remission with autologous stem cell transplant. This treatment strategy likely improves the outcome for patients compared with historical series; however, progression-free survival rates remain disappointing, ranging from 40% to 50%. This is currently an exciting time in the treatment of PTCL due to the advent of recently approved drugs as well as new targeted agents currently under investigation. In addition, gene expression profiling is allowing for a better understanding of underlying disease biology, improved diagnostic accuracy, and prognostication in PTCL. As a result, over the next few years, we expect a significant shift in our management of these diseases with a move toward more individualized therapy leading to improved outcomes.
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PMID:How I treat the peripheral T-cell lymphomas. 2461 79

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).
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PMID:Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. 2481 Jun 25

Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term "peripheral T-cell lymphomas". According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK(+)), and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK(-)). Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.
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PMID:Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations. 2619 Apr 36

Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.
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PMID:Treatment of Peripheral T-Cell Lymphoma: Many Shades of Gray. 2628 39


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