No abstract

This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.

Previous clinical trials based on the genetic correction of purified CD34(+) cells with gamma-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34(+) cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34(+) cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34(-) mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs).

Recent advances in therapy for pediatric hematologic neoplasms have greatly improved the prognosis but have resulted in an increased incidence of associated complications and toxic effects. The main neuroimaging features in pediatric patients with leukemia or lymphoma treated with chemotherapy or radiation therapy were retrospectively reviewed. To simplify the approach and facilitate differential diagnosis, the neuroimaging features have been classified into three main categories: central nervous system manifestations of primary disease, side effects of therapeutic procedures (radiation therapy, chemotherapy, bone marrow transplantation), and complications due to immunosuppression, particularly infections. Manifestations of primary disease include cerebrovascular complications (hemorrhage, cerebral infarction) and central nervous system involvement (infiltration of the meninges, parenchyma, bone marrow, orbit, and spine). Effects of radiation therapy include white matter disease, mineralizing microangiopathy, parenchymal brain volume loss, radiation-induced cryptic vascular malformations, and second neoplasms. Effects of chemotherapy and bone marrow transplantation include hemorrhage, dural venous thrombosis, white matter disease, reversible posterior leukoencephalopathy syndrome, and anterior lumbosacral radiculopathy. Both the underlying malignancy and antineoplastic therapy can cause immunosuppression. Fungi are the most frequent causal microorganisms in immunosuppressed patients with infection. Familiarity with the imaging findings is essential for proper diagnosis of neurologic symptoms in pediatric patients with oncohematologic disease.

Caspofungin, an echinocandin antifungal agent, is active against invasive Aspergillus and Candida infections. In a phase I study in healthy volunteers, mild transient increases in serum aminotransferases were observed with the concomitant administration of caspofungin and cyclosporin A (CsA). As a result, it is recommended that the concomitant use of the two drugs be limited to those settings with appropriate risk-benefit balance. We retrospectively assessed safety data in 14 patients with refractory invasive mycoses who were treated concomitantly with CsA and caspofungin before the drug was licensed in Spain. In all, 13 patients were adults (median age, 31.5 years; range, 14-67 years). The average duration of concomitant therapy was 15 days (range, 2-43 days). No clinically significant elevations of serum aminotransferases were observed, and no patient had concomitant therapy discontinued or interrupted due to a drug-related adverse event. In this study of a limited number of patients, the coadministration of caspofungin and CsA was generally well tolerated.