No abstract

Malignant astrocytomas are highly infiltrative neoplasms that invade readily into regions of normal brain. On a cellular basis, the motility and invasiveness of human cancers can be ascribed in part to complex rearrangements of the actin cytoskeleton that are governed by several actinbinding proteins. One such actin-binding protein that has been linked to the invasive behavior of carcinomas is fascin, which serves to aggregate F actin into bundles. In this study, we examined the expression of fascin in a series of human malignant astrocytomas (WHO grades I-IV). Five grade I, 5 grade II, 10 grade III, and 26 grade IV human astrocytomas were examined for fascin and glial fibrillary acidic protein (GFAP) expression by double immunofluorescence confocal microscopy. Expression of fascin and GFAP was also determined by Western blot analysis. Fascin expression increased with increasing WHO grade of astrocytoma. This is in marked contrast to GFAP expression, which decreased with increasing WHO grade. In grades I and II neoplasms, and within non-neoplastic brain, fascin and GFAP were expressed diffusely within regions examined. However, in the higher-grade astrocytomas (grades III and IV), fascin and GFAP were expressed regionally in distinctly separate tumor cell populations. This is the first study to demonstrate the expression of fascin in human astrocytic neoplasms. The role that fascin plays in contributing to the invasive phenotype of anaplastic astrocytomas awaits further study and investigation.

No abstract

111 In-DTPA-human epidermal growth factor ( 111 In-DTPA-hEGF [DTPA is diethylenetriaminepentaacetic acid]) is an Auger electron-emitting radiopharmaceutical that targets EGF receptor (EGFR)-positive cancer. The purpose of this study was to determine the effect of EGFR inhibition by gefitinib on the internalization, nuclear translocation, and cytotoxicity of 111 In-DTPA-hEGF in EGFR-overexpressing MDA-MB-468 human breast cancer cells. Methods: Western blot analysis was used to determine the optimum concentration of gefitinib to abolish EGFR activation. Internalization and nuclear translocation of fluorescein isothiocyanate-labeled hEGF were evaluated by confocal microscopy in MDA-MB-468 cells (1.3 · 10 6 EGFRs/cell) in the presence or absence of 1 mM gefitinib. The proportion of radioactivity partitioning into the cytoplasm and nucleus of MDA-MB-468 cells after incubation with 111 In-DTPA-hEGF for 24 h at 37°C in the presence or absence of 1 mM gefitinib was measured by cell fractionation. DNA double-strand breaks caused by 111 In were quantified using the g-H2AX assay, and radiation-absorbed doses were estimated. Clonogenic survival assays were used to measure the cytotoxicity of 111 In-DTPA-hEGF alone or in combination with gefitinib. Results: Gefitinib (1 mM) completely abolished EGFR phosphorylation in MDA-MB-468 cells. Internalization and nuclear translocation of fluorescein isothiocyanatelabeled EGF were not diminished in gefitinib-treated cells compared with controls. The proportion of internalized 111 In that localized in the nucleus was statistically significantly greater when 111 In-DTPA-hEGF was combined with gefitinib compared with 111 In-DTPA-hEGF alone (mean 6 SD: 26.0% 6 5.5% vs. 14.6% 6 4.0%, respectively; P , 0.05). Induction of g-H2AX foci was greater in MDA-MB-468 cells that were treated with 111 In-DTPA-hEGF (250 ng/mL, 1.5 MBq/mL) plus gefitinib (1 mM) compared with those treated with 111 In-DTPA-hEGF alone (mean 6 SD: 35 6 4 vs. 24 6 5 foci per nucleus, respectively). In clonogenic assays, a significant reduction in the surviving fraction was observed when 111 In-DTPA-hEGF (5 ng/mL, 6 MBq/mg) was combined with gefitinib (1 mM) compared with 111 In-DTPA-hEGF alone (42.9% 6 5.7% vs. 22.9% 6 3.6%, respectively; P , 0.01). Conclusion: The efficacy of 111 In-DTPA-hEGF depends on internalization and nuclear uptake of the radionuclide. Nuclear uptake, DNA damage, and cytotoxicity are enhanced when 111 In-DTPA-hEGF is combined with gefitinib. These results suggest a potential therapeutic role for peptide receptor radionuclide therapy in combination with tyrosine kinase inhibitors.

Hydrofluoric acid (HF) causes a unique chemical burn. Much of the current treatment knowledge of HF burns is derived from case reports, small case series, animal studies and anecdotal evidence. The management can be challenging because clinical presentation and severity of these burns vary widely. Plastic surgeons managing burn patients must have a basic understanding of the pathophysiology, the range of severity in presentation and the current treatment options available for HF burns. The present article reviews the current understanding of the pathophysiology and systemic effects associated with severe HF burns. Furthermore, it distinguishes between minor and life-threatening HF burns and describes several of the basic techniques that are available to treat patients with HF burns.