Heat-shock protein 70-dependent dendritic cell activation by 5-aminolevulinic acid-mediated photodynamic treatment of human glioblastoma spheroids in vitro

Background:

T-cell responses contribute to the anti-tumoural effect of photodynamic therapy (PDT). For such responses to occur, dendritic cells (DCs) have to migrate to the tumour, take up tumour antigens and respond to danger signals with maturation, before they engage in T-cell activation. Here, we have studied the effect of 5-aminolevulinic acid (ALA)-mediated PDT on DCs in vitro in a human spheroid model of glioblastoma (GB).

Methods:

Spheroids of the GB cell lines U87 and U251 were treated with ALA/PDT, and effects on attraction, uptake of tumour antigens and maturation of DCs were studied. To block heat-shock protein-70 (HSP-70) on the spheroids, neutralising antibodies were used.

Results:

5-Aminolevulinic acid /PDT-treated GB spheroids attracted DCs that acquired tumour antigens from the spheroids effectively. Moreover, co-culture with ALA/PDT-treated spheroids induced DC maturation as indicated by the upregulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the DCs. Heat-shock protein-70 was upregulated on the spheroids after ALA/PDT treatment. Uptake of tumour antigens and DC maturation induced by the ALA/PDT-treated spheroids were inhibited when HSP-70 was blocked.

Conclusion:

ALA/PDT treatment of glioma spheroids promotes the three initial steps of the afferent phase of adaptive immunity, which is at least partially mediated by HSP-70.     

Do patients undergo changes of their personality due to visual field defects? An investigation with FPI-R and NEI-VQ

BACKGROUND: Visual restrictions can lead to anxiety and possibly to social retirement. Therefore it makes sense to assess the patients' degree of handicap. The goal of the present study was to investigate if patients show changes in their personality or a reduced quality of life as a result of their visual field defect. METHODS: 15 patients with visual field defects were asked to fill out the revised version of the Freiburger Pers?nlichkeitsinventar (FPI-R) and the National Eye Institute Visual Function Questionnaire (NEI-VFQ). The FPI-R encompasses the standardised recording of many personality traits whereas the NEI-VFQ addresses the visual quality of life. RESULTS: In the total sample all FPI-R scales were appropriate for the study in the inconspicuous standard range. Slight shifts resulted toward increased willingness to make contacts (scale 4, ST 4.2), reduced physical strain (scale 7, ST 4.3) and lower physical discomfort (scale 8, ST 3.7). The size of the visual field defect does not correlate with the satisfaction with life, with the physical discomfort and with the state of health but with the dependency on others (p = 0.047) and with the exertion of their social roles (p = 0.043). The scale "satisfaction with life" of the FPI-R correlated with the scale "psychic condition" of the NEI-VFQ (p = 0.028) and the physical discomfort showed a significant correlation with the scale "eye strain" (p = 0.006) in the NEI-VFQ. DISCUSSION: Contrary to our presumptions, patients with visual field defects did not show any changes in their personality. It is supposed that they have learned to compensate for their reduced visual functions.     

Non-invasive electrical brain stimulation: from acute to late-stage treatment of central nervous system damage

Non-invasive brain current stimulation(NIBS) is a promising and versatile tool for inducing neuroplasticity,protection and functional rehabilitation of damaged neuronal systems.It is technically simple,requires no surgery,and has significant beneficial effects.However,there are various technical approaches for NIBS which influence neuronal networks in significantly different ways.Transcranial direct current stimulation(t DCS),alternating current stimulation(ACS) and repetitive transcranial magnetic stimulation(r TMS) all have been applied to modulate brain activity in animal experiments under normal and pathological conditions.Also clinical trials have shown that t DCS,r TMS and ACS induce significant behavioural effects and can – depending on the parameters chosen – enhance or decrease brain excitability and influence performance and learning as well as rehabilitation and protective mechanisms.The diverse phaenomena and partially opposing effects of NIBS are not yet fully understood and mechanisms of action need to be explored further in order to select appropriate parameters for a given task,such as current type and strength,timing,distribution of current densities and electrode position.In this review,we will discuss the various parameters which need to be considered when designing a NIBS protocol and will put them into context with the envisaged applications in experimental neurobiology and medicine such as vision restoration,motor rehabilitation and cognitive enhancement.     

The combination of carmustine wafers and temozolomide for the treatment of malignant gliomas. A comprehensive review of the rationale and clinical experience

Current treatment strategies in patients with newly-diagnosed glioblastoma include surgical resection with post-operative radiotherapy and concomitant/adjuvant temozolomide (the “Stupp protocol”) or resection with implantation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) wafers in the surgical cavity followed by radiotherapy. In clinical practice, patients with malignant glioma treated with BCNU wafer often also receive adjuvant temozolomide. However, current treatment guidelines are unclear on whether and how these treatment practices can be combined, and no prospective phase 3 study has assessed the safety and efficacy of combining BCNU wafers with temozolomide and radiation in high-grade malignant glioma. The rationale for multimodal therapy comprising surgical resection with adjunct local BCNU wafers followed by radiotherapy and temozolomide is based on complementary and synergistic mechanisms of action between BCNU and temozolomide in preclinical studies; a shared primary resistance pathway, methylguanine-DNA methyltransferase (MGMT); and the opportunity to overcome resistance through MGMT depletion to boost cytotoxic activity. A comprehensive review of the literature identified 19 retrospective and prospective studies investigating the use of this multimodal strategy. Median overall survival in 14 studies of newly-diagnosed patients suggested a modest improvement versus resection followed by Stupp protocol or resection with BCNU wafers, with an acceptable and manageable safety profile.     

Is there a role for sentinel lymph node biopsy in the management of sarcoma?

Is there a role for sentinel lymph node (SLN) biopsy in the management of sarcoma? Sentinel node biopsy has dramatically changed the management of melanoma and breast cancer, helping surgeons avoid radical lymphadenectomies in node negative patients who would previously have undergone a more morbid operation with little benefit, or remained pathologically unstaged. Many investigators have explored the use of lymphatic mapping for malignancies other than breast cancer or melanoma. Lymphatic mapping and sentinel node biopsy has not been investigated in the management of sarcomas, which is not surprising given that the majority of sarcomas spread by local extension or hematogenously. Regional lymph node metastases are rare; developing in about 3-10% of patients with localized disease. However, among certain subtypes of high-grade sarcomas there is a propensity for regional lymph node metastases. These include rhabdomyosarcoma, epithelioid sarcoma, clear cell sarcoma, synovial sarcoma, and vascular sarcomas. It is in these particular subtypes that there may be a benefit to SLN biopsy.     

Comparison of F-FET and F-FDG PET in brain tumors

The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [¹⁸F]-fluorodeoxyglucose (¹⁸F-FDG) and O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) in patients with brain lesions suspicious of cerebral gliomas.

Methods

Fifty-two patients with suspicion of cerebral glioma were included in this study. From 30 to 50 min after injection of 180 MBq ¹⁸F-FET, a first PET scan (¹⁸F-FET scan) was performed. Thereafter, 240 MBq ¹⁸F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection (¹⁸F-FET/¹⁸F-FDG scan). The cerebral accumulation of ¹⁸F-FDG was calculated by decay corrected subtraction of the ¹⁸F-FET scan from the ¹⁸F-FET/¹⁸F-FDG scan. Tracer uptake was evaluated by visual scoring and by lesion-to-background (L/B) ratios. The imaging results were compared with the histological results and prognosis.

Results

Histology revealed 24 low-grade gliomas (LGG) of World Health Organization (WHO) Grade II and 19 high-grade gliomas (HGG) of WHO Grade III or IV, as well as nine others, mainly benign histologies. The gliomas showed increased ¹⁸F-FET uptake (>normal brain) in 86% and increased ¹⁸F-FDG uptake (>white matter) in 35%. ¹⁸F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with ¹⁸F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with ¹⁸F-FET in 76% and with ¹⁸F-FDG in 28%. The L/B ratios showed significant differences between LGG and HGG for both tracers but considerable overlap so that reliable preoperative grading was not possible. A significant correlation of tracer uptake with overall survival was found with ¹⁸F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques.

Conclusions

¹⁸F-FET PET is superior to ¹⁸F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of ¹⁸F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like ¹⁸F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.     

Controlled release of dopamine from a polymeric brain implant: in vivo characterization

Intracerebral microdialysis was used to evaluate the long-term in vivo release of dopamine from ethylene-vinyl acetate (EVAc)-dopamine copolymer matrix discs for up to 65 days following striatal implantation. Dopamine release occurred through a single cavity present on one side of the disc, which was otherwise fully coated with an additional, impermeable layer of EVAc. At 20 days following implantation of the device, extracellular concentrations of dopamine within the striatum reached micromolar levels, over 200-fold greater than control values. Release of dopamine was shown to be stable and maintained for the 2-month duration of the experiment. Histological examination confirmed the biocompatible nature of the implant. There are potential applications of this technology to the treatment of Parkinson's disease and other neurological and psychiatric disorders.     

Controlled release of dopamine from a polymeric brain implant: In vitro characterization

A biocompatible polymeric matrix system for the long-term controlled release of dopamine has been developed. Solid particles of this bioactive agent were encapsulated in ethylene-vinyl acetate copolymer (EVAc). Following immersion in an aqueous buffer solution, the release rate of dopamine from the polymer matrix was found to depend on the initial concentration of dopamine in the polymer. After coating the matrix devices with an additional impermeable layer of EVAc, constant rates of release were obtained by creating a cavity in this impermeable layer. The observed experiments are consistent with a diffusion-limited model of dopamine release; all the in vitro experimental results were therefore correlated by the effective diffusion co-efficient of dopamine through the porous polymer network. These results are discussed in terms of potential design modifications to achieve desired release characteristics for a variety of neuroactive substances, including neurotransmitters or their precursors.