Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blast phase (BP) may occur as a late event in essential thrombocythemia (ET). This study includes 19 patients with post-ET BP diagnosed and followed in a single institution. At BP, 63% of patients had leukocytosis (white blood cell count >10 x 10(9)/L), 74% had anemia (hemoglobin value <10 g/dL), 74% had thrombocytopenia (platelet count <100 x 10(9)/L), and 84% were over 65 years of age. Cytogenetic analysis was available in 10 patients: six had karyotype aberrations. According to cytogenetic-based risk stratification of de novo acute leukemia (AL), all patients had an unfavorable profile. JAK2 (V617F) mutational status was evaluated in five patients. In two of them, the JAK2 mutation was undetectable in blast cells (one with JAK2-positive ET), whereas in three both granulocytes and blast cells displayed the mutation. Treatment of BP was patient-based according to the performance status and co-morbidities and consisted of palliation in 14 patients, and of induction of remission in five. Median survival was 2.3 months (range 0.2-22.3), irrespective of the treatment received. In conclusion, this study indicates that AL evolved from ET has unfavorable clinical and biological features. JAK2 (V617F)-positive ET may evolve in few instances into JAK2-negative leukemia. The outcome of patients is poor whatever the treatment used.
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PMID:Blast phase of essential thrombocythemia: A single center study. 1969 Nov 3

Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.
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PMID:JAK2 inhibitors: A reality? A hope? 1977 62

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
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PMID:[Classification of myeloid leukemias]. 1986 Jan 79

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2(V617F)) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2(V617F)-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.
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PMID:Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. 2000 98

Polycythemia vera (PV) is a common cause of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). The postpartum period is a precipitating cofactor. An additional heparin-induced thrombocytopenia/thrombosis (HIT/T) leads to a life-threatening condition in which transjugular intrahepatic portosystemic shunting (TIPS) seems to be the only life-saving procedure. We describe the case of a subacute BCS and PVT in the late postpartum period. The diagnosis was established using CT scan, MRI, and Doppler ultrasonography of abdominal vessels and the laboratory findings were compatible with PV. After a successful creation of TIPS, a HIT/T worsened the hemorrhagic and thrombotic picture. TIPS procedure was successfully repeated and heparin was replaced with Fondaparinux and then vitamin K antagonist. The treatment with interferon alpha-2A, started after the normalization of liver functions, resulted in a complete remission within 6 months. The JAK2 V617F mutation clone remained undetectable after 2 years' follow-up.
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PMID:Budd-Chiari syndrome and heparin-induced thrombocytopenia in polycythemia vera: successful treatment with repeated TIPS and interferon alpha. 2016 Mar 69

Managing patients with myelofibrosis (MF)-either those with primary MF or those whose MF has evolved from antecedent polycythemia vera or essential thrombocythemia-presents many challenges to the hematologist. Cure is potentially achievable through allogeneic stem cell transplantation, but this therapy is either inappropriate or not feasible for most patients. MF patients suffer from a range of debilitating disease manifestations (eg, massive splenomegaly, cytopenias, constitutional symptoms, and transformation to a treatment-refractory blast phase). Currently available therapies are palliative but can be of significant value to some MF patients for anemia, splenomegaly, or sometimes both manifestations. New medical therapies for MF revolve around three main themes: immunomodulation (to assist anemia), hypomethylation strategies, and (the most robust pipeline) the use of targeted JAK2 inhibitors. These latter agents have shown the ability to improve MF-associated splenomegaly and MF-associated symptoms but do not improve (and may exacerbate) anemia or thrombocytopenia. Future targeted agents, and perhaps combinations of agents that currently show complementary benefits, are anticipated to further enhance the efficacy of medical therapy for MF.
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PMID:New drugs for the treatment of myelofibrosis. 2042 92

Patients with HIV-1 immune-related thrombocytopenia have a unique antibody (Ab) against integrin GPIIIa49-66 capable of inducing oxidative platelet fragmentation via Ab activation of platelet nicotinamide adenine dinucleotide phosphate oxidase and 12-lipoxygenase releasing reactive oxygen species. Using a phage display single-chain antibody (scFv) library, we developed a novel human monoclonal scFv Ab against GPIIIa49-66 (named A11) capable of inducing fragmentation of activated platelets. In this study, we investigated the in vivo use of A11. We show that A11 does not induce significant thrombocytopenia or inhibit platelet function. A11 can prevent the cessation of carotid artery flow produced by induced artery injury and dissolve the induced thrombus 2 hours after cessation of blood flow. In addition, A11 can prevent, as well as ameliorate, murine middle cerebral artery stroke, without thrombocytopenia or brain hemorrhage. To further optimize the antithrombotic activity of A11, we produced a bifunctional A11-plasminogen first kringle agent (SLK), which homes to newly deposited fibrin strands within and surrounding the platelet thrombus, reducing effects on nonactivated circulating platelets. Indeed, SLK is able to completely reopen occluded carotid vessels 4 hours after cessation of blood flow, whereas A11 had no effect at 4 hours. Thus, a new antithrombotic agent was developed for platelet thrombus clearance.
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PMID:Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus. 2088 9

Isolated thrombocytopaenia can occur in 30-60% of HIV-infected patients. The majority of patients with HIV-related immune thrombocytopaenia have only minor submucosal bleeding problems. Cases of subarachnoid haemorrhage and subdural haematoma are very rare and management of such cases is a challenging problem for physicians. We report a rare case of subdural haematoma due to thrombocytopaenia in a 40-year-old HIV-positive man.
Int J STD AIDS 2010 Jun
PMID:Subdural haematoma: an uncommon presentation of thrombocytopaenia in HIV infection. 2060 28

Imatinib, a tyrosine kinase inhibitor (TKI) of BCR-ABL, was the standard first-line therapy for chronic myeloid leukemia (CML) for almost 10 years. Dasatinib and nilotinib, two newer drugs with higher potency than imatinib against BCR-ABL and activity against most imatinib-resistant BCR-ABL mutations, have each shown superior efficacy compared with imatinib for first-line treatment of chronic-phase CML in randomized phase 3 trials. With 14 months follow-up time, available data suggest no obvious differences in efficacy between dasatinib and nilotinib. Compared with imatinib, dasatinib is associated with higher rates of pleural effusion and thrombocytopenia, but lower rates of edema, gastrointestinal AEs, musculoskeletal AEs, and rash. Nilotinib is associated with higher rates of dermatologic toxicity, headache, and biochemical abnormalities associated with hepatic and pancreatic toxicity compared with imatinib, but lower rates of edema, gastrointestinal AEs, muscle spasm, and neutropenia. Several studies have shown that poor adherence to imatinib detrimentally affects responses and should be considered in patients with a suboptimal response. The different dosing requirements of dasatinib (once daily with or without food) and nilotinib (twice daily with fasting) may be an additional factor in selecting frontline agents. This review compares and contrasts the three FDA approved first line TKI agents.
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PMID:First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. 2110 51

A 52-year-old woman presented with isolated thrombocytosis in 2003. After 5 years of observation under a tentative diagnosis of essential thrombocythemia (ET), she was referred to our hospital because of anemia and leukopenia. Bone marrow biopsy demonstrated increases of megakaryocytes and myelofibrosis, but splenomegaly was absent. A karyotype study of bone marrow detected t(9;22) (q34;q11.2) in 6 of the 20 metaphases studied. Peripheral blood neutrophil BCA-ABL fusion signals (FISH) were not detected. Because RT-PCR assay of bone marrow detected major-BCR-ABL mRNA (b3a2), treatment with imatinib (400 mg/day) was started. After transient thrombocytopenia, normalization of blood cell counts and improvement of myelofibrosis were achieved. JAK2 V617F mutation and M-BCR-ABL mRNA was negative in peripheral blood. Clinical and laboratory data suggest that this case represents a rare and atypical myeloproliferative neoplasm with BCR-ABL translocation restricted mainly to the megakaryocyte lineage.
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PMID:[Atypical myeloproliferative neoplasm with a small population of Philadelphia chromosome-positive clones in the bone marrow]. 2140 27


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