Overcoming the blood brain barrier in glioblastoma: Status and future perspective.

Glioblastoma is the most common primary brain malignancy in adults. Treatment of glioblastoma patients is based on neurosurgery, radiation therapy and chemotherapy. Despite this multimodal therapeutic regimen, the prognosis of glioblastoma patients is poor. Indeed, glioblastoma is very resistant to treatments due to multiple molecular and cellular mechanisms including the existence of the blood-brain barrier (BBB). The BBB consists of multiple layers surrounding brain vessels and limits drug penetration within the brain. Therefore, overcoming the BBB is a strategy to increase bioavailability and efficacy of therapeutic agents against glioblastoma cells. The development of two approaches is ongoing: i) enhancing the delivery of drugs to the brain and ii) improving the penetration of drugs into the brain. One way to enhance drug delivery to the brain is through high-dose intravenous chemotherapy, with or without bone marrow transplantation, or via intra-arterial chemotherapy, with or without disrupting the BBB through osmotic means. Conversely, improving drug penetration within the brain can be achieved through modifying either the drug itself or the BBB. Promising results in terms of safety and signals of efficacy were obtained with these approaches in early phase clinical trials. More advanced comparative clinical trials are needed to investigate the clinical benefit for glioblastoma patients.

A DERATING METHOD FOR THERAPEUTIC APPLICATIONS OF HIGH INTENSITY FOCUSED ULTRASOUND.

Current methods of determining high intensity focused ultrasound (HIFU) fields in tissue rely on extrapolation of measurements in water assuming linear wave propagation both in water and in tissue. Neglecting nonlinear propagation effects in the derating process can result in significant errors. In this work, a new method based on scaling the source amplitude is introduced to estimate focal parameters of nonlinear HIFU fields in tissue. Focal values of acoustic field parameters in absorptive tissue are obtained from a numerical solution to a KZK-type equation and are compared to those simulated for propagation in water. Focal waveforms, peak pressures, and intensities are calculated over a wide range of source outputs and linear focusing gains. Our modeling indicates, that for the high gain sources which are typically used in therapeutic medical applications, the focal field parameters derated with our method agree well with numerical simulation in tissue. The feasibility of the derating method is demonstrated experimentally in excised bovine liver tissue.

FOCUSING OF HIGH POWER ULTRASOUND BEAMS AND LIMITING VALUES OF SHOCK WAVE PARAMETERS.

In this work, the influence of nonlinear and diffraction effects on amplification factors of focused ultrasound systems is investigated. The limiting values of acoustic field parameters obtained by focusing of high power ultrasound are studied. The Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation was used for the numerical modeling. Solutions for the nonlinear acoustic field were obtained at output levels corresponding to both pre- and post- shock formation conditions in the focal area of the beam in a weakly dissipative medium. Numerical solutions were compared with experimental data as well as with known analytic predictions.

Justifying adjuvant chemotherapy in breast cancer: a survey of women and healthcare professionals.

AIM: The absolute survival gains required to make adjuvant chemotherapy acceptable to women are unknown. We questioned women and healthcare professionals on the absolute survival benefits required to make adjuvant chemotherapy acceptable. METHODS: A cohort of 1000 Irish women and 402 UK nurses and surgeons were invited to choose an absolute survival advantage sufficient to justify adjuvant cytotoxic chemotherapy. The non-physician cohort included women with a history of cancer, female medical healthcare professionals and women with no personal or professional experience of cancer. RESULTS: Eight hundred and thirty-five women completed the questionnaire; 769, 651 and 413 said they would accept chemotherapy for a 10%, 5% and 1% survival advantage, respectively. There was a significant difference in women's preferences depending on their personal and professional experience of cancer. Eighty-nine women had personal experience of chemotherapy and these women were more likely to accept chemotherapy for any survival advantage (88, 87 and 66 for a 10%, 5% and 1% survival advantage, respectively; p=0.0023; Chi(2)). Surgeons and nurses were less likely to accept chemotherapy for smaller absolute survival advantages. CONCLUSIONS: This study confirms that women require modest absolute gains to choose adjuvant chemotherapy. The pattern of acceptance differs significantly between those with professional experience of cancer, a personal history of chemotherapy use and a history of cancer or not.

The effects of MK-801, ifenprodil, JO 1784, JO 1994 and JO 1997 on PK 11195 receptor binding, nitric oxide synthase (NO synthase) activity and infarct volume in a mouse model of focal cerebral ischaemia.

Middle cerebral artery occlusion (MCAO) is a widely used surgical procedure for inducing focal cortical ischaemia in mice. In the present study, all experiments were performed on 4-week-old, male Swiss mice (OF-1 Iffa Credo, France), 20-25 g at the time of surgery. Sham-operated mice were subjected to simple exposure of the middle cerebral artery. Mice were injected with either MK-801, ifenprodil, JO 1784, JO 1994 or JO 1997 at the following time points after surgery; 5, 15, 45 min and 3, 6, 24, 30, 48 and 54 h. Mice were sacrificed 72 h after surgery and both ipsilateral and contralateral cortices were dissected in their entirety, weighed, and assayed for [3H]PK 11195 binding while the brain-stem and cerebellum were assayed for nitric oxide synthase (NO synthase) activity. In a separate experiment the area of ischaemic damage was determined planimetrically by means of an image analysis system. Coagulation of the middle cerebral artery induced a marked enhancement of the ipsilateral cortical omega 3 peripheral-type benzodiazepine binding site (PTBB'S) densities, an increase in NO synthase activity in the brain-stem and cerebellum, and an increase in the cortical infarct area. MK-801, ifenprodil, JO 1784, JO 1994 and JO 1997 demonstrated comparable neuroprotective effects on all three indices of cortical damage. A down-regulation of cortical omega 3 peripheral-type benzodiazepine binding site (PTBB'S) densities and a decrease in NOS activity occurred following pharmacological intervention. In contrast to JO 1784, JO 1994 and JO 1997 have a bimodal effect on omega 3 PTBB'S densities.

The novel sigma ligand JO 1994 protects against ischaemia-induced behavioural changes, cell death and receptor dysfunction in the gerbil.

To assess the effects of the novel sigma ligand JO 1994 on behavioural, histological and autoradiographical changes following global ischaemia, the Mongolian gerbil was used. Three experiments were carried out and in each case ischaemia was induced by bilateral carotid occlusion (BCO) for 5 min. In the first experiment we examined the effects of JO 1994 administered at doses of 0.25, 0.5 and 1 mg/kg i.p. 1 h before 5 min BCO on histological parameters 96 h after surgery. In the second experiment the effects of JO 1994 administered at doses of 2.5, 5, 10 and 20 mg/kg i.p. 1 h before 5 min BCO on locomotor activity 24, 48 and 72 h after surgery and on histological parameters 96 h after surgery was examined. In the third experiment the effects of JO 1994 (2.5 and 5 mg/kg i.p.), BMY 14802 (1 and 10 mg/kg i.p.) and MK-801 (2.5 mg/kg i.p.) administered 30 min, 6, 24, 48, 72, 96 and 120 h post-surgery on the densities of M1 and M2 muscarinic receptors in 35 brain regions, 7 days after surgery was examined. Results indicated that 5 min bilateral carotid occluded animals were hyperactive 24, 48 and 72 h after surgery. JO 1994 attenuated this hyperactivity. Extensive neuronal death was observed in the CA1 layer of the hippocampus in 5 min BCO animals 96 h after surgery. The low doses of JO 1994 (0.25, 0.5 and 1 mg/kg) had no effect on the ischaemia-induced cell death. However JO 1994 (2.5, 5, 10 and 20 mg/kg i.p.) protected against the neuronal death of cells in the CA1 layer (P < 0.01-0.03). There was a large loss of M1 and M2 receptors in the CA1 regions of the hippocampus. MK-801, BMY 14802 and JO 1994 provided significant (P < 0.01) protection against this ischaemia-induced receptor loss.

The sigma receptor ligand JO 1784 (igmesine hydrochloride) is neuroprotective in the gerbil model of global cerebral ischaemia.

To assess the effects of the novel sigma receptor ligand JO 1784 ((+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-yl-but-3-en-1-ylami ne, hydrochloride or igmesine hydrochloride) on behavioural and histological changes following cerebral ischaemia, the gerbil model of cerebral ischaemia was used. Two experiments were carried out. In the first animals were either sham operated, subjected to 5 min of bilateral carotid occlusion or administered JO 1784 (25, 50, 75 or 100 mg/kg p.o.) 1, 24 and 48 h after 5 min bilateral carotid occlusion and histological evaluation carried out 96 h after surgery. In the second experiment the effects of JO 1784 administered at a dose of 100 mg/kg i.p. 30 min, 6, 24 and 48 h post-surgery on home cage activity and nitric oxide (NO) synthase activity in the cortex, hippocampus, cerebellum and brain stem 4 days after surgery was examined. Extensive neuronal death was observed in the CA1 region of 5 min occluded animals. JO 1784 (50, 75 and 100 mg/kg) provided significant protection against this ischaemia-induced cell death (P < 0.03-0.005). In the second experiment a large increase in home cage activity was observed for 5 min occluded animals for 12 h after surgery (P = 0.0018-0.02). A large increase in NO synthase activity was observed in all brain regions for 5 min occluded animals. Post-administration of JO 1784 attenuated the ischaemia-induced hyperactivity and increased NO synthase activities.(ABSTRACT TRUNCATED AT 250 WORDS)