Pathogenesis of cerebral malformations in human fetuses with meningomyelocele

<p>Abstract</p> <p>Background</p> <p>Fetal spina bifida aperta (SBA) is characterized by a spinal meningomyelocele (MMC) and associated with cerebral pathology, such as hydrocephalus and Chiari II malformation. In various animal models, it has been suggested that a loss of ventricular lining (neuroepithelial/ependymal denudation) may trigger cerebral pathology. In fetuses with MMC, little is known about neuroepithelial/ependymal denudation and the initiating pathological events.</p> <p>The objective of this study was to investigate whether neuroepithelial/ependymal denudation occurs in human fetuses and neonates with MMC, and if so, whether it is associated with the onset of hydrocephalus.</p> <p>Methods</p> <p>Seven fetuses and 1 neonate (16–40 week gestational age, GA) with MMC and 6 fetuses with normal cerebral development (22–41 week GA) were included in the study. Identification of fetal MMC and clinical surveillance of fetal head circumference and ventricular width was performed by ultrasound (US). After birth, MMC was confirmed by histology. We characterized hydrocephalus by increased head circumference in association with ventriculomegaly. The median time interval between fetal cerebral ultrasound and fixing tissue for histology was four days.</p> <p>Results</p> <p>At 16 weeks GA, we observed neuroepithelial/ependymal denudation in the aqueduct and telencephalon together with sub-cortical heterotopias in absence of hydrocephalus and/or Chiari II malformation. At 21–34 weeks GA, we observed concurrence of aqueductal neuroepithelial/ependymal denudation and progenitor cell loss with the Chiari II malformation, whereas hydrocephalus was absent. At 37–40 weeks GA, neuroepithelial/ependymal denudation coincided with Chiari II malformation and hydrocephalus. Sub-arachnoidal fibrosis at the convexity was absent in all fetuses but present in the neonate.</p> <p>Conclusion</p> <p>In fetal SBA, neuroepithelial/ependymal denudation in the telencephalon and the aqueduct can occur before Chiari II malformation and/or hydrocephalus. Since denuded areas cannot re-establish cell function, neuro-developmental consequences could induce permanent cerebral pathology.</p

VEGF-SPECT with 111In-bevacizumab in stage III/IV melanoma patients

Purpose: A feasibility study was performed to investigate the presence of VEGF in melanoma lesions by VEGF-SPECT with In-111-bevacizumab. In addition the effect of a single therapeutic bevacizumab dose on In-111-bevacizumab uptake was compared with VEGF levels in resected melanoma lesions. Patients and methods: Eligible were patients with stage III/IV melanoma who presented with nodal recurrent disease. VEGF-SPECT was performed after administration of 100 Mbq (111) In-bevacizumab (8 mg) at days 0, 2, 4 and 7 post injection. Tumour visualisation and quantification were compared with CT and FDG-PET. On day 7 a single dose of 7.5 mg/kg bevacizumab was administered intravenously. On day 21, a second tracer dose In-111-bevacizumab was administered and scans were obtained on days 21, 25 and 28. Metastases were surgically resected within 2 weeks after the last VEGF-SPECT scan and immunohistological (IHC) VEGF tumour expression was compared with In-111-bevacizumab tumour uptake. Results: Nine patients were included. FOG-PET and CT detected both in total 12 nodal lesions which were all visualised by VEGF-SPECT. At baseline, In-111-bevacizumab tumour uptake varied 3-fold between and 1.6 +/- 0.1-fold within patients. After a therapeutic dose of bevacizumab there was a 21 +/- 4% reduction in In-111-bevacizumab uptake. The In-111-bevacizumab tumour uptake in the second series positively correlated with the VEGF-A expression in the resected tumour lesions. Conclusion: VEGF-SPECT could visualise all known melanoma lesions. A single dose of bevacizumab slightly lowered In-111-bevacizumab uptake. Future studies should elucidate the role of VEGF-SPECT in the selection of patients and the individual dosing of bevacizumab treatment. (C) 2011 Elsevier Ltd. All rights reserved