Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier

Background

Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.

Methods

Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (K^trans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.

Results

In all 14 evaluable patients, K^trans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1–3 weeks before decreasing to baseline by 6 weeks.

Conclusions

The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1–2 weeks after laser ablation and resolving by 4–6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01851733","term_id":"NCT01851733"}}NCT01851733     

Nectary Structure and Ultrastructure of Unisexual Flowers of Ecballium elaterium(L.) A. Rich. (Cucurbitaceae) and their Presumptive Pollinators

The structure and ultrastructure of the nectaries of the monoeciousspecies Ecballium elaterium were studied. Large differencesin size and structure of the nectaries were observed in thetwo genders of flowers, those of the staminate flowers beingmuch larger and more developed than those of the pistillateflowers. The latter do not secrete measurable amounts of nectar.In the nectariferous cells, especially of the staminate flowers,numerous plasmodesmata are present. The pre-nectar originatingin the phloem is stored in the plastids of the nectariferouscells primarily as starch grains. The nectar appears to be exudedfrom the nectary via modified stomata. Very small insects ofthe order Hemiptera were found to dwell inside the flowers ofthe two genders, but in different numbers; their number in thestaminate flowers was more than twice that in the pistillateflowers. These insects may take part in the process of pollination.Copyright 2001 Annals of Botany Company Ecballium elaterium, Cucurbitaceae, monoecious plant, nectaries, structure, ultrastructure, nectar secretion, stomata, Hemiptera insects     

Rapid fluorescent assay for screening drugs on Leishmania amastigotes

A rapid fluorescent viability assay employing alamarBlue was optimized for use with Leishmania axenic amastigotes, the stage of the parasite responsible for disease pathology. The activity of two protein kinase inhibitors, Staurosporine and H-89, as well as Amphotericin B, on promastigotes and amastigotes of Leishmania donovani and Leishmania tropica was compared. Both protein kinase inhibitors inhibited promastigote growth at lower concentrations than amastigotes, while the GI(50) for Amphotericin B on both stages was similar. This assay only requires a limited number of axenic amastigotes (50,000 cells/well) and can be used to rapidly screen large chemical or natural product libraries for activity against amastigotes.     

A new Heck reaction modification using ketone Mannich bases as enone precursors: parallel synthesis of anti-leishmanial chalcones

A new Heck-type reaction for the synthesis of chalcones has been established using Mannich bases as enone precursors. The novel reaction proceeds rapidly in air atmosphere under ligandless conditions and can be adapted for library synthesis in a parallel reactor station. Screening of the synthesized chalcones revealed N-{4-[(1E)-3-oxo-3-(3-pyridinyl)-1-propenyl]phenyl}benzamide (3f) to be a potent anti-leishmanial agent.     

Temperature-dependent electrical resistivity of the hornet cuticle: Changes induced by colchicine and purine in the diet

Various cuticular areas of the Oriental hornet (Vespa orientalis) were measured for their electrical resistivity within the range of 3–40°C. It was found that: (1) the electrical resistivity is temperature dependent; (2) there are no significant differences in this respect between hornets collected in different regions; (3) there are no differences in the electrical resisitivity between the yellow and brown areas of the cuticle in control hornets; (4) there are however, significant changes in resistance between the yellow and brown strips of hornets fed on purine; (5) hornets fed on colchicine reach a minimum resistance at a higher temperature than do the control hornets; and (6) hornets fed on purine reach a minimum resistance at a lower temperature. It is suggested that the cuticular changes in resistivity at different temperatures reflect the hornets' mechanism of detecting and adjusting to changes in the ambient temperature.     

Temperature dependence of the electrical resistivity of social wasp cuticle: A comparative study

Resistance to electricity by social wasp cuticle is temperature dependent within the range of 1–40°C. This was measured on the species Vespa orientalis (the Oriental hornet), Vespa crabro (the European hornet) and the wasp Dolichovespula saxonica. The resistance at first decreases with increased temperature, reaching a nadir which differs according to species, and then rises again up to 40°C, the highest temperature tested. It is suggested that the cuticular changes in resistivity at different temperatures reflect the wasp's mechanism for detecting and regulating the temperature in their normal environment.     

Early brain vulnerability in Wolfram syndrome

Wolfram Syndrome (WFS) is a rare autosomal recessive disease characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, deafness, and neurological dysfunction leading to death in mid-adulthood. WFS is caused by mutations in the WFS1 gene, which lead to endoplasmic reticulum (ER) stress-mediated cell death. Case studies have found widespread brain atrophy in late stage WFS. However, it is not known when in the disease course these brain abnormalities arise, and whether there is differential vulnerability across brain regions and tissue classes. To address this limitation, we quantified regional brain abnormalities across multiple imaging modalities in a cohort of young patients in relatively early stages of WFS. Children and young adults with WFS were evaluated with neurological, cognitive and structural magnetic resonance imaging measures. Compared to normative data, the WFS group had intact cognition, significant anxiety and depression, and gait abnormalities. Compared to healthy and type 1 diabetic control groups, the WFS group had smaller intracranial volume and preferentially affected gray matter volume and white matter microstructural integrity in the brainstem, cerebellum and optic radiations. Abnormalities were detected in even the youngest patients with mildest symptoms, and some measures did not follow the typical age-dependent developmental trajectory. These results establish that WFS is associated with smaller intracranial volume with specific abnormalities in the brainstem and cerebellum, even at the earliest stage of clinical symptoms. This pattern of abnormalities suggests that WFS has a pronounced impact on early brain development in addition to later neurodegenerative effects, representing a significant new insight into the WFS disease process. Longitudinal studies will be critical for confirming and expanding our understanding of the impact of ER stress dysregulation on brain development.