The phosphatidyl-inositol 3 kinase (PI3k)/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, ...we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in nonresponder samples. Anthracyclines activate nuclear factor κB (NF-κB), and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-κB in ALL samples. Using a short interfering (si) RNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-κB activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-κB was overexpressed. In conclusion, rapamycin targets 2 pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts—PI3k/Akt through the mammalian target of rapamycin and NF-κB through FKBP51—suggesting that the drug could be beneficial in the treatment of childhood ALL. (Blood. 2005;106:1400-1406)
Central nervous system (CNS) complications during treatment of childhood acute lymphoblastic leukemia (ALL) remain a challenging clinical problem. Outcome improvement with more intensive chemotherapy ...has significantly increased the incidence and severity of adverse events. This study analyzed the incidence of neurological complications during ALL treatment in a single pediatric institution, focusing on clinical, radiological, and electrophysiological findings. Exclusion criteria included CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy, late-onset encephalopathy, or long-term neurocognitive defects. During a 9-year period, we retrospectively collected 27 neurological events (11%) in as many patients, from 253 children enrolled in the ALL front-line protocol. CNS complications included posterior reversible leukoencephalopathy syndrome (n = 10), stroke (n = 5), temporal lobe epilepsy (n = 2), high-dose methotrexate toxicity (n = 2), syndrome of inappropriate antidiuretic hormone secretion (n = 1), and other unclassified events (n = 7). In conclusion, CNS complications are frequent events during ALL therapy, and require rapid detection and prompt treatment to limit permanent damage.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A form of autosomal dominant macrothrombocytopenia is characterized by mild or no clinical symptoms, normal platelet function, and normal megakaryocyte count. Because this condition has so far ...received little attention, patients are subject to misdiagnosis and inappropriate therapy. To identify the molecular basis of this disease, 12 Italian families were studied by linkage analysis and mutation screening. Flow cytometry evaluations of platelet membrane glycoproteins (GPs) were also performed. Linkage analysis in 2 large families localized the gene to chromosome 17p, in an interval containing an excellent candidate, the GPIbα gene. GPIbα, together with other proteins, constitutes the plasma von Willebrand factor (vWF) receptor, which is altered in Bernard-Soulier syndrome (BSS). In 6 of 12 families, a heterozygous Ala156Val missense substitution was identified. Platelet membrane GP studies were performed in 10 patients. Eight were distinguished by a reduction of GPs comparable to that found in a BSS heterozygous condition, whereas the other 2, without the Ala156Val mutation, had a normal content of platelet GPs. In conclusion, the current study provides evidence that most (10 of 12) patients with an original diagnosis of autosomal dominant macrothrombocytopenia shared clinical and molecular features with the heterozygous BSS phenotype. The remaining 2 affected subjects represented patients with “true” autosomal dominant macrothrombocytopenia; the GPIb/IX/V complex was normally distributed on the surface of their platelets. Thus, the diagnosis of heterozygous BSS must always be suspected in patients with inherited thrombocytopenia and platelet macrocytosis.
Summary
The transcription factor GATA-1, together with its cofactor FOG-1, regulates erythropoiesis and megakaryocytopoiesis. Mutations in the DNA or FOG-1 binding sites of its N-terminal zinc finger ...result in different illnesses. Alterations of the FOG-1 face are responsible for dyserythropoietic anemia with thrombocytopenia while R216Q, the only mutation identified in the DNA face, induces X-linked thrombocytopenia with thalassemia (XLTT). The former disorder has been studied in detail whereas little is known about the latter since only one family has been investigated. We studied a second family with an R216Q, showing that XLTT and dyserythropoietic anemia with thrombocytopenia, even if different clinical entities, are closely related disorders. In both cases, patients present mild dyserythropoiesis, red cell hemolysis, severely defective maturation of megakaryocytes, macrothrombocytopenia with α-granule deficiency, and abnormalities of the cytoplasmic membrane system. However, a thalassemia minor phenotype has only been described in patients with XLTT whereas severe anemia and thrombocytopenia with evident defects of platelet composition and function may be observed only in dyserythropoietic anemia with thrombocytopenia.
Summary
Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that ...evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) 88·0% in Arm B; 83·9% in Arm C (P = 0·72), and 42/48 at low risk (87·5%) 87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41). None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8–15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.
In Fanconi anemia (FA) C mice tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) have key roles in the pathogenesis of bone marrow failure. In FA subjects TNF-α was found to be increased in the ...serum and overproduced by patient-derived B-cell lines. In acquired aplastic anemia, a disease in which, similarly to FA, marrow failure occurs, TNF-α and IFN-γ act as late mediators of the stem cell damage and are overexpressed in patient marrow lymphocytes. This study evaluated in marrow mononuclear cells (MNCs) of patients with FA, the expression of negative modulators of the hematopoiesis, such as TNF-α, IFN-γ, macrophage inflammatory protein 1α (MIP-1α), and surface Fas ligand, and the role of TNF-α on FA erythropoiesis in vitro. TNF-α and IFN-γ were significantly overexpressed in stimulated marrow MNCs of FA patients as compared to healthy controls. MIP-1α and Fas ligand were undetectable in patients and controls. In bone marrow cultures, the addition of anti–TNF-α increased the size and significantly increased the number of erythroid colony-forming units and erythroid burst-forming units grown from FA patients but not from healthy controls. This indicates that FA subjects have a marrow TNF-α activity that inhibits erythropoiesis in vitro. TNF-α has a relevant role in the pathogenesis of erythroid failure in FA patients.
Idiopathic pulmonary hemosiderosis is a chronic, rare disorder confined to the lung, which is commonly characterized by the triad of recurrent hemoptysis, diffuse parenchyma infiltrates on chest ...radiography, and iron-deficiency anemia. Diagnosis may be difficult and the clinical course may be widely variable. Here, we describe an 8-year-old boy whose isolated symptom on presentation was iron-deficiency anemia. Presence of hemoptysis and bilateral alveolar infiltrates on chest x-ray led to the diagnosis of pulmonary hemosiderosis, subsequently confirmed by the finding of hemosiderin-laden macrophages by bronchoalveolar lavage. The patient was started on prednisolone 2 mg/kg/d and no further bleeding episodes were noted after the onset of therapy.
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