Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mTOR (mammalian target of rapamycin) serine threonine kinase is involved in the regulation of the cell cycle, apoptosis and angiogenesis. mTOR inhibitors (rapamycin, or analogues such as CCI-779, RAD001, AP23573), which have been shown to have a potent anti-neoplastic effect in many solid tumor models, are now being used in clinical trials. Recent data have shown that the mTOR pathway is also aberrantly activated in hematological malignancies including acute myeloid leukemia (AML). This disease still has a bad prognosis and new therapeutic strategies are required. Rapamycin, used at low concentrations, induces the profound inhibition of AML cell clonogenic properties in 60% of cases while sparing their normal counterparts. Moreover, clinical responses have been achieved in poor-risk AML patients. In this review, we discuss the possible mechanisms of mTOR activation, the mechanisms involved in the inhibition of cell proliferation by rapamycin, the possible resistance mechanisms and ways of improving rapamycin efficacy in the context of AML.
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PMID:mTOR, a new therapeutic target in acute myeloid leukemia. 1620 24

Myeloid sarcoma (MS) is an invasive extramedullary solid tumor composed of immature cells of the myeloid series. It complicates the clinical course of a minority of patients with acute myeloid leukemia (AML). Traditionally its presence has been regarded as an indicator of aggressive disease. Currently, the optimal treatment of AML with concurrent MS remains to be determined. We report two cases of autologous bone marrow transplantation (auto-BMT) for AML with concurrent MS followed by a review of the literature.
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PMID:Acute myeloid leukemia with concurrent myeloid sarcoma treated with autologous bone marrow transplantation: two illustrative cases and a literature review. 1627 93

Malignant Hodgkin's lymphoma (HL) has become a curable disease through the increasing intensity of the treatment strategies applied. These regimens are aggressive, including radiotherapy and chemotherapy leading to the possibility of secondary malignancies. The German Hodgkin Lymphoma Study Group considered three cohorts including 5,411 patients with all stages of HL. In 127 patients a secondary solid tumor was diagnosed (cumulative risk 2%, median follow-up 72 months), with bronchial carcinomas (23.6%) and colorectal adenocarcinomas (20.5%) being the most frequent neoplasms. Secondary acute myeloid leukemia was found in 36 patients, another ten developed myeloid dysplasia (cumulative risk 1%, median follow-up 55 months). A total of 52 patients revealed a non-Hodgkin's lymphoma (NHL; cumulative risk 0.9%, median follow-up 46 months). The overall incidence of secondary malignancies was 3.9% in patients who had been treated successfully for their HL with radio- and/or chemotherapy.A secondary NHL can be particularly difficult to be distinguished from the preceding HL. Therefore, in case of a suspected relapse, a complete histopathological work-up must be performed.
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PMID:[Secondary malignancies after successful primary treatment of malignant Hodgkin's lymphoma]. 1636 61

Secreted protein, acidic and rich in cysteine (SPARC), is a matricellular glycoprotein with growth-inhibitory and antiangiogenic functions. Although SPARC has been implicated as a tumor suppressor in humans, its function in normal or malignant hematopoiesis has not previously been studied. We found that the leukemic cells of AML patients with MLL gene rearrangements express low to undetectable amounts of SPARC whereas normal hematopoietic progenitors and most AML patients express this gene. SPARC RNA and protein levels were also low or undetectable in AML cell lines with MLL translocations. Consistent with its tumor suppressive effects in various solid tumor models, exogenous SPARC protein selectively reduced the growth of cell lines with MLL rearrangements by inhibiting cell cycle progression from G1 to S phase. The lack of SPARC expression in MLL-rearranged cell lines was associated with dense promoter methylation. However, we found no evidence of methylation-based silencing of SPARC in primary patient samples. Our results suggest that low or absent SPARC expression is a consistent feature of AML cells with MLL rearrangements and that SPARC may function as a tumor suppressor in this subset of patients. A potential role of exogenous SPARC in the therapy of MLL-rearranged AML warrants further investigation.
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PMID:Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein. 1642 66

PRAME is expressed at low levels in normal testes and highly in solid tumor cells and hematological malignancies. The purpose of this study was to investigate PRAME expression levels in children with acute leukemia with real-time PCR analysis. Seventeen children with newly diagnosed or relapsed acute leukemia (11 ALL, 4 AML, 1 acute myeloblastic leukemia secondary to MDS, 1 ALL at relapse) and a control group of seven children were studied. Overexpression of PRAME was found in 52.9% (3 AML, 6 ALL) of the patients studied. No important correlation between PRAME expression and the patients' prognosis was observed. The above findings indicate that PRAME expression in acute leukemia does not seem to be of prognostic significance, whereas it might represent a candidate marker for the monitoring of minimal residual disease.
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PMID:Quantitative assessment of PRAME expression in diagnosis of childhood acute leukemia. 1686 Aug 64

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, occurs in nearly all patients with polycythemia vera (PV) but also in a variable proportion of patients with other myeloid disorders; mutational frequency is estimated at approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF), up to 20% in certain subcategories of atypical myeloproliferative disorder (atypical MPD), less than 3% in de novo myelodysplastic syndrome (MDS) or acute myeloid leukemia, and 0% in chronic myeloid leukemia (CML). Accordingly, there is now molecular justification for grouping PV, ET, and MF together in a distinct MPD category (i.e., classic, BCR-ABL(-) MPD) that is separate from chronic myeloid leukemia (CML), MDS, and atypical MPD. To date, JAK2V617F has not been described in patients with reactive myeloproliferation, lymphoid disorders, or solid tumor. Therefore, the presence of JAK2V617F strongly suggests an underlying MPD and it is therefore reasonable to consider JAK2V617F-based laboratory tests for the evaluation of polycythemia, primary thrombocytosis, unexplained leukocytosis, bone marrow fibrosis, or abdominal vein thrombosis. Current information on disease-specific prognostic relevance of JAK2V617F is inconclusive and confounded by inter-study differences in the performance of mutation screening assays. Regardless, the discovery of JAK2V617F has reinforced the pathogenetic contribution of JAK-STAT signaling in MPD and identifies JAK2 as a valid drug target.
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PMID:Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. 1712 67

This prospective, two-site, randomized, controlled pilot study assessed the feasibility of an enhanced physical activity (EPA) intervention in hospitalized children and adolescents receiving treatment for a solid tumor or for acute myeloid leukemia (AML), and assessed different statistical techniques to detect the intervention's sleep and fatigue outcomes. Twenty-nine patients (25 with a solid tumor and 4 with AML) participated. Data were collected from actigraph; patient, parent, and staff nurse reports of patient fatigue; parent sleep diaries; and patient charts. The intervention was successfully implemented 85.4% of the scheduled times. We used two different statistical methods to analyze the longitudinal data. Using an ANOVA model, sleep was significantly more efficient in the experimental arm than in the control arm when daily differences from baseline sleep efficiency values were averaged and compared (F=4.17, P=0.053). However, in a mixed model (repeated measures) analysis, sleep duration (F=0.54, P=0.47) and sleep efficiency (F=0.04, P=0.85) were not seen to differ between study arms. We conclude that an inpatient intervention of EPA can be delivered to children and adolescents receiving chemotherapy. Our findings identify design and statistical considerations for a future effectiveness study of the EPA intervention in hospitalized pediatric oncology patients.
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PMID:Clinical field testing of an enhanced-activity intervention in hospitalized children with cancer. 1736 Jan 51

Intrathecal (IT) treatment of neoplastic meningitis secondary to relapsed or refractory malignancies is a major challenge for clinicians. We studied feasibility and toxicity of IT administered liposomal cytarabine on a compassionate basis in 5 patients (male, n=4; female, n=1; age at diagnosis 5 to 18 y) with recurrent acute lymphoblastic leukemia (n=3), primary refractory acute myeloid leukemia (n=1), or relapsed medulloblastoma (n=1). All of them had evidence of meningeal involvement as shown by presence of leukemic blasts or solid tumor cells on cytologic examination of cerebrospinal fluid and were refractory to standard central nervous system (CNS) therapy. A total of 33 doses were given. Leukemic blasts or solid tumor cells were cleared from cerebrospinal fluid in all patients. IT liposomal cytarabine was well tolerated in 2 patients, but may have contributed to neurologic side effects in 2 other patients with 1 patient who received high-dose methotrexate 96 hours before IT liposomal cytarabine developing transient encephalopathy. Another patient experienced seizures after 6 well-tolerated doses of IT liposomal cytarabine. In the fifth patient, treatment with IT liposomal cytarabine was not continued after a single dose because of toxic cauda equina syndrome, resulting from previous intensive CNS therapy. If administered simultaneously to other neurotoxic drugs, IT liposomal cytarabine may contribute to neurologic side effects in patients who had received prior intensive CNS-directed therapy. IT liposomal cytarabine should, therefore, be used cautiously, if a patient receives other potentially neurotoxic drugs simultaneously.
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PMID:Feasibility and toxicity of intrathecal liposomal cytarabine in 5 children and young adults with refractory neoplastic meningitis. 1741 63

Sweet's syndrome (the eponym for acute febrile neutrophilic dermatosis) is characterized by a constellation of clinical symptoms, physical features, and pathologic findings which include fever, neutrophilia, tender erythematous skin lesions (papules, nodules, and plaques), and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis. Several hundreds cases of Sweet's syndrome have been published. Sweet's syndrome presents in three clinical settings: classical (or idiopathic), malignancy-associated, and drug-induced. Classical Sweet's syndrome (CSS) usually presents in women between the age of 30 to 50 years, it is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease and pregnancy. Approximately one-third of patients with CSS experience recurrence of the dermatosis. The malignancy-associated Sweet's syndrome (MASS) can occur as a paraneoplastic syndrome in patients with an established cancer or individuals whose Sweet's syndrome-related hematologic dyscrasia or solid tumor was previously undiscovered; MASS is most commonly related to acute myelogenous leukemia. The dermatosis can precede, follow, or appear concurrent with the diagnosis of the patient's cancer. Hence, MASS can be the cutaneous harbinger of either an undiagnosed visceral malignancy in a previously cancer-free individual or an unsuspected cancer recurrence in an oncology patient. Drug-induced Sweet's syndrome (DISS) most commonly occurs in patients who have been treated with granulocyte-colony stimulating factor, however, other medications may also be associated with DISS. The pathogenesis of Sweet's syndrome may be multifactorial and still remains to be definitively established. Clinical and laboratory evidence suggests that cytokines have an etiologic role. Systemic corticosteroids are the therapeutic gold standard for Sweet's syndrome. After initiation of treatment with systemic corticosteroids, there is a prompt response consisting of dramatic improvement of both the dermatosis-related symptoms and skin lesions. Topical application of high potency corticosteroids or intralesional corticosteroids may be efficacious for treating localized lesions. Other first-line oral systemic agents are potassium iodide and colchicine. Second-line oral systemic agents include indomethacin, clofazimine, cyclosporine, and dapsone. The symptoms and lesions of Sweet's syndrome may resolved spontaneously, without any therapeutic intervention; however, recurrence may follow either spontaneous remission or therapy-induced clinical resolution.
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PMID:Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis. 1765 51

A case-control study was conducted to investigate the role of a familial history of cancer in the etiology of childhood acute leukemia. The history of cancer in the relatives of 472 cases was compared with that of 567 population-based controls. Recruitment was frequency matched on age, sex and region. The familial history of cancer in each child's relatives was reported by the mother in response to a standardized self-administered questionnaire. A familial history of solid tumor in first or second-degree relatives was associated with an increased risk of acute lymphoblastic leukemia (odds ratio (OR)=1.6 [95% confidence interval, 1.2-2.1]), while a familial history of hematopoietic malignancies in first or second-degree relatives was associated with an increased risk of acute myeloid leukemia (OR=4.3 [1.4-13]). The ORs for the histories of cancer increased with the number of relatives with cancer (OR=1.5 [1.1-2.0] for one relative and OR=2.3 [1.3-3.8] for two relatives or more; Ptrend<0.0001). Significant associations between childhood acute leukemia and familial history of genital cancers and brain tumor were also observed (OR=2.7 [1.2-5.8] and OR=10.7 [1.3-86], respectively). This study supports the hypothesis that a familial history of cancer may play a role in the etiology of childhood acute leukemia. It also evidences some specific associations that require further investigation.
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PMID:Familial history of cancer and childhood acute leukemia: a French population-based case-control study. 1792 19


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