Phase II window of idarubicin in children with extraocular retinoblastoma.

PURPOSE: The aim of this study was to evaluate in an upfront phase II study the response to idarubicin in children with extraocular retinoblastoma. PATIENTS AND METHODS: The starting dose of idarubicin was 15 mg/m(2)/d (days 1 and 2) weeks 0 and 3. After an interim evaluation, the dose was reduced to 10 mg/m(2)/d (days 1 and 2) weeks 0 and 3 because of hematopoietic toxicity. Response was evaluated at week 6. RESULTS: At the Hospital JP Garrahan (Buenos Aires, Argentina), 10 patients (five bilateral) were entered onto the study from 1995 to 1998. A total of 19 cycles were administered. Extraocular sites included orbit (n = 10), bone marrow (n = 3), bone (n = 1), lymph node (n = 1), and CNS (n = 1). The response rate was 60% (95% confidence interval, 30% to 90%). One complete response was achieved, in addition to five partial responses, two cases of stable disease, and two cases of progressive disease. All patients with bone marrow involvement achieved complete clearance of tumor cells. The patient with CNS disease had progressive disease. All patients had severe hematopoietic toxicity (grade 4 neutropenia and grade 3/4 thrombocytopenia after most cycles). Other toxicities included grade 2 diarrhea in 30%. No echocardiographic changes were detected. CONCLUSION: Idarubicin is active in extraocular retinoblastoma. The activity of this drug should be explored in future phase III studies.     

Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF(V600E)-induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF(V600E)-driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15(INK4B). This treatment also eliminated subpopulations resistant to targeted BRAF(V600E) inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF(V600E) inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.     

Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project

Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.     

Acoustic Emission Monitoring of Progressive Damage of Reinforced Concrete T-Beams under Four-Point Bending

Acoustic Emission (AE) is revealed to be highly adapted to monitor materials and structures in materials research and for site monitoring. AE-features can be either analyzed by means of physical considerations (geophysics/seismology) or through their time/frequency waveform characteristics. However, the multitude of definitions related to the different parameters as well as the processing methods makes it necessary to develop a comparative analysis in the case of a heterogeneous material such as civil engineering concrete. This paper aimed to study the micro-cracking behavior of steel fiber-reinforced reinforced concrete T-beams subjected to mechanical tests. For this purpose, four-points bending tests, carried out at different displacement velocities, were performed in the presence of an acoustic emission sensors network. Besides, a comparison between the sensitivity to damage of three definitions corresponding to the b-value parameter was performed and completed by the evolution of the RA-value and average frequency (AF) as a function of loading time. This work also discussed the use of the support-vector machine (SVM) approach to define different damage zones in the load-displacement curve. This work shows the limits of this approach and proposes the use of an unsupervised learning approach to cluster AE data according to physical and time/frequency parameters. The paper ends with a conclusion on the advantages and limitations of the different methods and parameters used in connection with the micro/macro tensile and shear mechanisms involved in concrete cracking for the purpose of in situ monitoring of concrete structures.     

Gitelman syndrome,hypomagnesemia, and venous thrombosis: An intriguing association

Among salt‐wasting tubulopathies'' complications, venous thrombosis is one of the rarest. We report a case of a young woman with Gitelman syndrome (GS). She presented a deep venous thrombosis in her leg and was treated with heparin with favorable outcomes. We retained hypomagnesemia as the cause of the thrombosis.     

<Emphasis Type="Italic">GATA2</Emphasis> gene analysis in several forms of hematological malignancies including familial aggregations

The genetic predisposition to familial hematological malignancies has been previously reported highlighting inherited gene mutations. Several genes have been reported but genetic basis remains not well defined. In this study, we extended our investigation to a potential candidate GATA2 gene which was analyzed by direct sequencing in 119 cases including familial aggregations with a variety of hematological malignancies and sporadic acute leukemia belonging to Tunisian and French populations. We reported a deleterious p.Arg396Gln GATA2 mutation in one patient diagnosed with both sporadic acute myeloid leukemia (AML) and breast cancer. We also reported several GATA2 variations in familial cases. The absence of deleterious mutations in this large cohort of familial aggregations of hematological malignancies may strengthen the hypothesis that GATA2 mutations are an important predisposing factor, although as a secondary genetic event, required for the development of overt malignant disease.     

Sternal metastasis revealing hepatocarcinoma

INTRODUCTION: Bone metastasis from hepatocarcinoma are rare, their elective seats are the ribs, the vertebra and rarely the sternum. We report a case of a sternal metastasis which makes discovery of a hepatocarcinoma. EXEGESIS: A 64 year-old man, alcoholic with a previous history of jaundice who developed since 1999 an anterior chest tumor with excellent clinical condition. Laboratory examination showed cytolysis, cholestasis, positive antihepatitis C virus antibodies and elevated serum alphafetoprotein level. Standard radiography and computed tomography of the chest showed an osteolytic lesion of the sternum spread to the adjacent soft tissues and voluminous right hepatic lesion. Pathologic examination of the sternal tumor concluded to a differential adenocarcinoma. Etiologic investigations to find the primitive tumor were negative. Operative procedure was not possible in consideration of the infiltration of the tumor and its situation near the main blood vessels. Radiotherapy gives rise to partial regression of the tumor. A second reading of the tumor biopsy established the diagnosis of metastasis from a hepatocellular carcinoma. The patient died 22 months after the appearance of the sternal metastasis. CONCLUSION: Hepatocarcinoma is rarely disclosed by a sternal metastasis, our case-report is particular by its prolonged survival and the good clinical condition during its follow up.     

Ultrafine particles affect experimental thrombosis in an in vivo hamster model

Particulate air pollution is associated with cardiovascular morbidity and mortality. To investigate this association, we studied the effect of ultrafine (60 nm) polystyrene particles on thrombus formation in a hamster model after intravenous and intratracheal administration of unmodified, carboxylate-polystyrene, or amine-polystyrene particles. Unmodified particles had no effect on thrombosis up to 5 mg/kg. Carboxylate-polystyrene particles significantly inhibited thrombus formation at 500 and 100 microg/kg body weight but not at 50 microg/kg body weight. In contrast, amine-polystyrene particles significantly enhanced thrombosis at 500 and 50 microg/kg body weight but not at 5 microg/kg body weight. Similarly, the intratracheal instillation of 5,000 microg of amine-polystyrene particles significantly increased thrombus formation. The unmodified particles and carboxylate-polystyrene particles had no effect. During platelet aggregation in human platelet-rich plasma, induced with 1.25 microM ADP, unmodified particles had no effect up to 100 microg/ml, and carboxylate-polystyrene particles weakly enhanced platelet aggregation at 25 to 100 microg/ml. However, amine-polystyrene particles (50 and 100 microg/ml) induced platelet aggregation themselves and strongly increased the ADP-induced aggregation. We conclude that the presence of (ultrafine) particles in the circulation may affect hemostasis. The observed in vivo prothrombotic tendency results, at least in part, from platelet activation by positively charged amine-polystyrene particles.