Patients with multiple schwannomas without vestibular schwannomas have been postulated to compose a distinct subclass of neurofibromatosis (NF), termed "schwannomatosis." To compare the molecular-genetic basis of schwannomatosis with NF2, we examined the NF2 locus in 20 unrelated schwannomatosis patients and their affected relatives. Tumors from these patients frequently harbored typical truncating mutations of the NF2 gene and loss of heterozygosity of the surrounding region of chromosome 22. Surprisingly, unlike patients with NF2, no heterozygous NF2-gene changes were seen in normal tissues. Examination of multiple tumors from the same patient revealed that some schwannomatosis patients are somatic mosaics for NF2-gene changes. By contrast, other individuals, particularly those with a positive family history, appear to have an inherited predisposition to formation of tumors that carry somatic alterations of the NF2 gene. Further work is needed to define the pathogenetics of this unusual disease mechanism.

No abstract

Neurofibromatosis type 2 (NF2) is a genetic disorder characterized by formation of multiple schwannomas and meningiomas due to inactivating mutations in the NF2 tumor suppressor gene on chromosome 22. We describe a polymorphism in the 3' untranslated region of the NF2 gene that is informative in about one-third of individuals. This polymorphism permitted an assessment of the relative expression of NF2 transcripts in lymphoblastoid cell RNA from 22 unrelated NF2 patients heterozygous for a germline NF2 mutation, along with 6 schwannomatosis patients, and 14 unaffected controls. Unequal allelic expression (1.8- to 20-fold) was detected in 15 of the NF2 cases, but in none of the schwannomatosis or control individuals. Underexpression of the NF2 mutant allele was documented for all 6 nonsense or frameshift mutations, 3 of 6 splice mutations, and 1 of 4 missense mutations, which, unexpectedly, was shown to alter the NF2 transcript and create a premature stop codon. In contrast, equal expression or slight overexpression of NF2 mutant alleles was observed for 2 in-frame deletions, 2 splice alterations, and 3 missense mutations. In the remaining 5 cases, the allele representing the mutant transcript was not known. Thus, truncating NF2 mutations, which are the most frequent alterations in NF2 patients and NF2-associated tumors, were associated with underexpression of the mutant allele, whereas the less common in-frame alterations usually showed normal or slight overexpression of the mutant transcript.

No abstract

BACKGROUND: Pediatric Diffuse intrinsic pediatric glioma (DIPG) remained dismal regardless of the new therapeutic and technical attempts. PURPOSE: To investigate the efficacy and toxicity of hypofractionated radiotherapy in pediatric DIPG compared to conventional radiotherapy and to determine the prognostic factors for its overall (OS) and progressionfree survival (PFS). PATIENTS AND METHODS: Sixty four children, below the age of 18 years, who presented to Children's Cancer Hospital, Egypt (CCHE) during the period July 2007 and July 2011 were randomized into 2 groups. The hypofractionated group received 39 Gy in 13 fractions in 21/2 weeks and the conventional arm receiving 55.8 Gy in 31 fractions in 6 weeks using conformal radiotherapy technique. The two arms were not different in age, gender, performance status and tumor volume. RESULTS: Thirty two children were randomized in each arm. The median OS for the whole group was 9.5 + 1.0 months: 7.4 + 1.0 months for the hypofractionated arm and 9.9 + 1.0 months for the conventional arm. The whole group has median PFS of 7.3 + 0.8 months; 7.0 + 1.4 months for the hypofractionated and 7.7 + 1.1 for the conventional arm. On the other hand, the 1-year and 2-year OS were 41.4 + 9.2% and 28.4 + 8,8% in the hypofractionated arm and 36.2 + 8.7% and 32.3 + 7.8% in the conventional arm. None of these differences was statistically significant. Furthermore, none of the tested factors (age, gender, performance status, tumor volume, radiation volume or tumor extension) proved to have statistically significant influence on OS or PFS. All patients showed marked degree of improvement in symptoms and signs with earlier response in the hypofractionated arm. The immediate and delayed side effects were not different between the 2 arms. CONCLUSIONS: Hypofractionated radiotherapy had similar overall, progression-free survival and delayed effect (in the long survivors) to conventional fractionation. It offers less burden on the patients, their families and the treating machines and departments.

In this study we investigated the mechanism responsible for the unresponsiveness of thymus-reactive T cells obtained from severe combined immunodeficient (SCID) mice constructed with human fetal liver (FL) stem cells from donor A and an allogeneic human fetal thymus (FT) from donor B (A/B SCID-hu mice). These A/B SCID-hu mice have a human thymus containing B cells, macrophages, and dendritic cells from FL donor A but thymic epithelial cells from FT donor B. The repertoire of human T cells developing in this chimeric thymus is depleted of T cells specific for the HLA Ags of the FL donor, whereas T cells reactive against the HLA Ags expressed by the FT donor are still present. However, these thymocytes failed to proliferate and expressed low levels of the activation markers CD25, CD71, and HLA-DR after stimulation with the EBV-LCL of the FT donor in primary MLRs. This unresponsiveness could be completely reversed by IL-2. Restoration of T cell responsiveness was Ag specific and a unique property of IL-2. The T cells produced very low levels of IL-2 when stimulated with the HLA Ags of FT donor B, whereas they secreted normal levels of IL-2 after activation by third party alloantigens. Low IL-2 production was also observed at the clonal level. CD4+ T cell clones from A/B SCID-hu mice, specific for the HLA Ags of B, produced significantly less IL-2 and granulocyte macrophage-CSF than control CD4+ T cell clones. However, these T cell clones synthesized normal levels of IL-2 and granulocyte macrophage-CSF after stimulation with combinations of PMA/Calo or PMA/anti-CD3 mAb. Thus, T cells that differentiate in a chimeric thymus containing allogeneic host thymic epithelium are rendered tolerant to the HLA Ags expressed by the thymic epithelial cells. This tolerance results in the presence of T cells that do not proliferate properly after Ag-specific stimulation. This lack of proliferation is primarily related to their inability to produce sufficient levels of IL-2 and can be restored by exogenous IL-2.

No abstract

No abstract