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An indwelling balloon applicator developed for postoperative intracavity afterloading brachytherapy was evaluated for photodynamic therapy (PDT). Following tumor resection, the applicator is positioned in the center of the resultant cavity and the balloon is inflated with a scattering solution. The liquid-filled balloon stabilizes the resection cavity ensuring a constant and simple geometric shape during treatment. The catheter is brought out through the skin and adjusted so that 1–2 cm projects above the scalp surface. Measurements of light distribution in a phantom model surrounding the balloon catheter, show that it may be used to deliver sufficiently uniform light doses during PDT. The light distribution is uniform to within 5% when the balloon is filled with a scattering medium. Based on simple assumptions, it is shown that the applicator can be used to deliver a sufficient optical dose to brain tissue at a depth of 1 cm in less than 1 h. The applicator has already been used for brachytherapy in 72 patients with few complications. A new treatment protocol employing the combination of both fractionated intracavity brachytherapy and PDT is currently being planned. [ABSTRACT FROM AUTHOR]

Two patients with recurrent medulloblastomas were treated with combined oral and intra-venous chemotherapy followed by intra-arterial BCNU. The 7 days course of oral and intra-venous chemotherapy consisted of CCNU and Procarbazin orally and Vincristine intra-venously (PCV), repeated after 6 weeks. Intra-arterial chemotherapy consisted of 4 cycles of BCNU. Both patients responded well to treatment, evaluated by CT scans. One of the patients died of a new local recurrence 6 months after initiation of chemotherapy, whereas the other patient remains well, without CT evidence of tumour 36 months after the start of the treatment. No serious adverse side-effects related to the treatment were seen. [ABSTRACT FROM AUTHOR]

We have cultured peripheral blood lymphocytes (PBL) from glioblastoma patients in recombinant interleukin-2 (IL-2) containing medium for a period of 5 days. The cytotoxicity of these cells was tested on Cr-labelled autologous dissociated glioblastoma cells which had not been cultured. Significant cytotoxicity against glioma cells was observed in seven out of nine cases. IL-2 activated PBL from normal donors were equally cytotoxic against these glioma cells. Autologous lymphocytes activated by phytohaemagglutinin were also lysed in most cases, and the erythroleukemia cell line K562 was highly susceptible to the cytotoxic capability of the IL-2 activated PBL. In cold target inhibition experiments, K562 inhibited the cytotoxicity against both autologous and allogenic glioma cells, and glioma cells inhibited the cytotoxicity against K562. Following immunomagnetic separation, the IL2 activated cells demonstrated cytotoxicity against glioma cells, K562 cells, and PHA blasts in both the CD8 and the CD8 subsets. [ABSTRACT FROM AUTHOR]

We report the prognostic significance of tumor CT contrast enhancement within histological subgroups in 831 consecutive adult glioma patients of high-grade (n=516) and low-grade (n=315) histology. In the present report, a negative prognostic factor is associated with shortened survival. Methods: Survival analysis including Kaplan-Meier plots, log-rank tests, Cox analysis, and Aalen's linear model as implemented in SPSS and S-PLUS. Results: Sensitivity and specificity of contrast enhancement as a test for high-grade glioma was 0.87 and 0.79, respectively. Enhancement was a strong negative prognostic factor comparable to high-grade histology in the total patient population. Enhancement was also a negative prognostic factor within the subgroups adult high-grade (Grade 3–4), anaplastic (Grade 3), and low-grade (Grade 1–2) gliomas (p < 0.001). The prognostic implications of initial enhancement declined in high-grade patients surviving beyond 36 months. Tumor contrast enhancement or calcifications (in parentheses) were present in 96% (3.6%) of glioblastomas, in 87% (7.4%) of high-grade gliomas, in 56.5% of anaplastic gliomas, and in 21% (16.2%) of low-grade gliomas. Calcification was a positive prognostic factor within the high-grade group of patients (p < 0.0001). Conclusion: Enhancement was a major prognostic factor comparable to high-grade histology in this glioma patient population. Enhancement was a negative prognostic factor within each of the adult subgroups high-grade, anaplastic (grade 3), and low-grade gliomas. Enhancement was strongly associated with but not pathognomonic for high-grade histology. [ABSTRACT FROM AUTHOR]

• Transfected macrophages (NR8383) can act as converter cells in gene-directed enzyme prodrug therapy. • Compared to glioma cells, macrophages demonstrated increased resistance to the effects of the produced active drug. • PCI greatly increased non-viral transfection efficiency of prodrug converter gene cytosine deaminase (CD) into macrophages. • Reduced glioma cell viability by co-culture with NR8383 when prodrug 5-fluorocytosine (5-FC) was present, but not absent. Drawn by tumor synthesis of chemo-attractive factors, macrophages are frequently found in and around glioblastomas and play an important role both in augmenting as well as inhibiting tumor growth. Patient-derived macrophages have the potential, therefore, to act as targeted delivery vectors for a variety of anti-cancer treatments. Among these is ex vivo gene transfection and re-injection back into the patient of macrophages to target residual tumors. In this study, photochemical internalization (PCI) is investigated as a technique for the non-viral transfection of the cytosine deaminase (CD) prodrug activating gene into macrophages. The CD gene encodes an enzyme that converts the nontoxic antifungal agent, 5-fluorocytosine (5-FC), into 5-fluorouracil (5-FU) – a potent chemotherapeutic agent. PCI (photosensitizer + light treatment) mediated CD gene transfection of rat alveolar Ma cells was carried out in vitro. CD gene transfected NR8383 macrophages were co-cultured with F98 rat glioma cells in the presence or absence of 5-FC. Cell viability was assayed using the MTS colorimetric assay. Compared to the glioma cells, NR8383 demonstrated enhanced resistance to the toxic effects of 5-FU. PCI greatly increased the transfection efficiency of the CD gene in NR8383 cells. The viability of F98 cells was significantly inhibited by coculture with CD transfected NR8383 macrophages and 5-FC. Although gene insertion into macrophages has proven difficult, the results presented here show that non-viral transfection of the CD gene into these immune cells can be enhanced via PCI. CD transfected NR8383 cells could efficiently convert 5-FC to 5-FU and export the drug, producing a pronounced bystander toxic effect on adjacent non-transfected glioma cells. Compared to single treatment, repetitive PCI-induced transfection was more efficient at low CD plasmid concentration. [ABSTRACT FROM AUTHOR]

In order to effectively apply nanoparticles to clinical use, macrophages have been used as vehicles to deliver genes, drugs or nanomaterials into tumors. In this study, the effectiveness of macrophage as a drug delivery system was validated by biodistribution imaging modalities at intercellular and ex vivo levels. We focused on biodistribution imaging, namely, the characterization of the gold nanoparticle-loaded macrophages using intracellular holotomography and target delivery efficiency analysis using ex vivo fluorescence imaging techniques. In more detail, gold nanoparticles (AuNPs) were prepared with trisodium citrate method and loaded into macrophage cells (RAW 264.7). First, AuNPs loading into macrophages was confirmed using the conventional ultraviolet-visible (UV-VIS) spectroscopy and inductively coupled plasma-mass spectrometry (ICP-MS). Then, the holotomographic imaging was employed to characterize the intracellular biodistribution of the AuNPs-loaded macrophages. The efficacy of target delivery of the well AuNPs uptake macrophages was studied in a mouse model, established via lipopolysaccharide (LPS)-induced inflammation. The fluorescent images and the ex vivo ICP-MS evaluated the delivery efficiency of the AuNPs-loaded macrophages. Results revealed that the holotomographic imaging techniques can be promising modalities to understand intracellular biodistribution and ex vivo fluorescence imaging can be useful to validate the target delivery efficacy of the AuNPs-loaded macrophages. [ABSTRACT FROM AUTHOR]

Photochemical internalisation (PCI) is a unique intervention which involves the release of endocytosed macromolecules into the cytoplasmic matrix. PCI is based on the use of photosensitizers placed in endocytic vesicles that, following light activation, lead to rupture of the endocytic vesicles and the release of the macromolecules into the cytoplasmic matrix. This technology has been shown to improve the biological activity of a number of macromolecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus and oligonucleotides and certain chemotherapeutics, such as bleomycin. This new intervention has also been found appealing for intracellular delivery of drugs incorporated into nanocarriers and for cancer vaccination. PCI is currently being evaluated in clinical trials. Data from the first-in-human phase I clinical trial as well as an update on the development of the PCI technology towards clinical practice is presented here. [ABSTRACT FROM AUTHOR]