Effect of systemic celecoxib on human meningioma after intracranial transplantation into nude mice.

BACKGROUND: Meningiomas are mostly benign, but they may have a notorious tendency to recur when total resection is not possible. Systemic chemotherapeutical treatment has been largely disappointing. The treatment of meningiomas with the cyclooxygenase-2 (COX-2) inhibitor celecoxib showed inhibitory-growth effects in vitro and in vivo after subcutaneous transplantation into mouse. So far, celecoxib has never been tested in an orthotopic model of meningioma. In this work, we tested the effects of celecoxib on the growth of human benign meningiomas after transplantation into the prefrontal cortex of nude mice after confirming the inhibitory in vitro effect on these cells. METHODS: Primary cell cultures were stereotactically implanted into mice and were treated with 0, 750, or 1,500 ppm celecoxib for 3 months. The mice were then killed and blood was analyzed for celecoxib concentration. The mice brains were histologically processed for measurement of tumor volume, COX-2 expression, proliferation index (PI), intratumoral microvessel density (iMVD), and vascular endothelial growth factor (VEGF) expression. RESULTS: Treatment with celecoxib had no effect on tumor volume, despite the fact that we found a dose-dependent inhibitory effect on cell cultures and there was a sufficiently high celecoxib concentration in blood plasma and brain tissue. Additionally, celecoxib had neither an effect on COX-2 and VEGF expression nor on the PI and iMVD. CONCLUSIONS: Our findings suggest that celecoxib may not be effective on meningioma growth in clinical settings. In general, these results may indicate that the effect of treatment on brain tumors should not only be tested in a heterotopic environment but also in the orthotopic location of these tumors.

DETERMINING THE DOSE RATE DEPENDENCE OF DIFFERENT ACTIVE PERSONAL DOSEMETERS IN STANDARDIZED PULSED AND CONTINUOUS RADIATION FIELDS.

In 2016, the EURADOS working group 12 started a project to gather reliable data concerning the behavior of active personal dosemeters (APDs) used by European hospitals in standardized pulsed and hospital fields. This paper concentrates on the tests that deal with the dose rate dependence of APDs in laboratory tests. The dependence on the dose rate was determined for 10 dosemeter types with continuous radiation of a 60Co source and pulsed radiation of the reference radiation facility of Physikalisch-Technische Bundesanstalt. Furthermore, irradiations were done with continuous radiation of a 137Cs source of the Karlsruher Institute of Technology and with continuous X-rays of the two radiation qualites in radiation beams emerging from the X-ray source assembly, RQR5 and RQR8, of Nofer Institute of Occupational Medicine. For the first time, APDs have been systematically investigated under laboratory conditions in a pulsed reference fields according to ISO/TS 18090-1 and the experience gained by these test procedures will be included in the new IEC/TS 63050.

TESTING DIFFERENT AREA DOSEMETERS CONCERNING THEIR BEHAVIOUR IN PULSED RADIATION FIELDS.

In Germany, authorised experts are required to measure around an X-ray facility to determine supervised and controlled areas within the scope of a legal regulatory procedure. For this purpose, they have to use area dosemeters which are nationally type-approved by the PTB according to the German measurement and verification act. To date, all available type-approved area dosemeters are only tested in continuous radiation fields, and therefore the technical data of the measuring instruments are valid only for continuous radiation. In practice, however, the majority of facilities use pulsed radiation X-rays. Since no other measuring equipment is available, the authorised experts use supposedly unsuitable dosemeters. But is this really so? In the scope of this article, instruments typically used for these measurements were tested to investigate their behaviour in pulsed radiation fields. The approach is similar to that of Friedrich et al.

Dose measurements in pulsed radiation fields with commercially available measuring components.

Dose measurements in pulsed radiation fields with dosemeters using the counting technique are known to be inappropriate. Therefore, there is a demand for a portable device able to measure the dose in pulsed radiation fields. As a detector, ionisation chambers seem to be a good alternative. In particular, using a secondary standard ionisation chamber in combination with a reliable charge-measuring system would be a good solution. The Physikalisch-Technische Bundesanstalt (PTB) uses secondary standard ionisation chambers in combination with PTB-made measuring electronics for dose measurements at its reference fields. However, for general use, this equipment is too complex. For measurements on-site, a mobile special electronic system [Hupe, O. and Ankerhold, U. Determination of ambient and personal dose equivalent for personnel and cargo security screening. Radiat. Prot. Dosim. 121: (4), 429-437 (2006)] has been used successfully. Still, for general use, there is a need for a much simpler but a just as good solution. A measuring instrument with very good energy dependence for H*(10) is the secondary standard ionisation chamber HS01. An easy-to-use and commercially available electrometer for measuring the generated charges is the UNIDOS by PTW Freiburg. Depending on the expected dose values, the ionisation chamber used can be selected. In addition, measurements have been performed by using commercially available area dosemeters, e.g. the Mini SmartION 2120S by Thermo Scientific, using an ionisation chamber and the Szintomat 6134 A/H by Automess, using a scintillation detector.

Comparative morphological and immunohistochemical study of human meningioma after intracranial transplantation into nude mice.

Although surgical resection of benign human meningiomas is the primary goal, in case of relapse or when they are not fully resectable, other strategies including chemotherapeutical treatment would be appropriate. The initial evaluation of chemotherapeutical agents requires an appropriate tumor model, where the natural characteristics of the original benign tumor is reflected. We here tested, whether primary cell cultures of benign human meningiomas would reliably grow after intracranial transplantation into mice, and whether they would show histomorphological and immunohistochemical characteristics of the original human tumor. Cells of 11 benign human meningiomas were transplanted into the prefrontal cortex of nude mice. After 3 months, the mice were sacrificed and their brains were histologically processed for morphological characterization and measurement of tumor volume. Additionally, the proliferation index (PI), the microvessel density, and epithelial membrane antigen (EMA) were compared between human meningiomas and tumors grown in mice by using immunohistochemical methods. Further, cyclooxygenase-2 (COX-2) expression, a possible target for pharmacological manipulation, was examined. The results showed in almost all mice (93%) a tumor formation with meningothelial histomorphology comparable to the original human tumors. The PI, vascular density and COX-2 expression were similar between human and mice meningiomas, but EMA expression was reduced in mice (P<0.01). In conclusion an implantation of benign human meningioma primary cell cultures in mice reliably results in tumor formation with morphological and immunohistological features comparable to the original human tumor. This model may therefore be suitable to test novel therapeutic agents.

Cyclooxygenase-2 supports tumor proliferation in vestibular schwannomas.

BACKGROUND: Recent studies have shown that cyclooxygenase-2 (COX-2) plays an important role in tumor growth and neovascularization. However, COX-2 expression in vestibular schwannomas (VSs) has not been investigated. OBJECTIVE: To analyze the pattern of COX-2 expression in sporadic and neurofibromatosis type 2 (NF2)-associated VSs and its relationship with tumor proliferation and microvessel density. METHODS: Fifteen sporadic and 15 NF2-associated VSs were examined for COX-2 expression, microvessel density, and proliferation rate by immunohistochemical methods. Immunohistochemical scores were used to interpret the extent and intensity of COX-2 staining. Microvessel density (MVD) was determined using von Willebrand factor (vWf). Proliferation rate was quantified using Ki-67. The relationship among COX-2 expression, MVD, and proliferation rate was statistically analyzed. RESULTS: COX-2 expression was detected in 29 (96.67%) of 30 VSs, with no significant difference between sporadic and NF2-associated VSs (P = .722). In 6 (20%) VSs, COX-2 expression was graded as strong, in 12 (40%) as moderate, and in 11 (36.7%) as weak. VSs with high proliferation showed significantly higher COX-2 expression (P = .015) than VSs with low proliferation. COX-2 expression and MVD did not show specific biological correlations (P = .035). CONCLUSION: Our data demonstrate that COX-2 is expressed in VSs. High COX-2 expression in VSs with high proliferation rates suggests that the COX-2 pathway may be involved in the development and growth of VSs.

Loss of the protein-tyrosine phosphatase DEP-1/PTPRJ drives meningioma cell motility.

DEP-1/PTPRJ is a transmembrane protein-tyrosine phosphatase which has been proposed as a suppressor of epithelial tumors. We have found loss of heterozygosity (LOH) of the PTPRJ gene and loss of DEP-1 protein expression in a subset of human meningiomas. RNAi-mediated suppression of DEP-1 in DEP-1 positive meningioma cell lines caused enhanced motility and colony formation in semi-solid media. Cells devoid of DEP-1 exhibited enhanced signaling of endogenous platelet-derived growth factor (PDGF) receptors, and reduced paxillin phosphorylation upon seeding. Moreover, DEP-1 loss caused diminished adhesion to different matrices, and impaired cell spreading. DEP-1-deficient meningioma cells exhibited invasive growth in an orthotopic xenotransplantation model in nude mice, indicating that elevated motility translates into a biological phenotype in vivo. We propose that negative regulation of PDGF receptor signaling and positive regulation of adhesion signaling by DEP-1 cooperate in inhibition of meningioma cell motility, and possibly tumor invasiveness. These phenotypes of DEP-1 loss reveal functions of DEP-1 in adherent cells, and may be more generally relevant for tumorigenesis.