Prophylactic enlargement of the thecal sac volume by spinal expansion duroplasty in patients with unresectable malignant intramedullary tumors and metastases prior to radiotherapy.

Unresectable malignant intramedullary tumors and metastases usually require radiotherapy which intensifies spinal cord edema and might result in neurological decline. Spinal expansion duroplasty before radiotherapy enlarges the intrathecal volume and might thus prevent neurological deficits. The study aims to evaluate the clinical course of patients undergoing expansion duroplasty. This retrospective analysis (2007-2016) included all patients with unresectable intramedullary tumors who underwent spinal expansion duroplasty. To assess the degree of preoperative cord enlargement, we calculated the "diameter ratio": diameter of the spinal cord below and above the tumor / diameter of the tumor × 2. The presence of perimedullary cerebrospinal fluid (CSF) at the affected levels was analyzed on the preoperative magnetic resonance imaging (MRI). We recorded the occurrence of neurological deficits, wound breakdown, and CSF fistula. We screened 985 patients, 11 of which were included. Eight patients had an intramedullary metastasis, three patients a spinal malignant glioma. A diameter ratio ≤ 0.8 representing a significant preoperative intramedullary enlargement was seen in 10 cases (90.9%). Postoperative imaging was available in 9 patients, demonstrating successful decompression in 8 of the 9 patients (88.9%). The postoperative course was uneventful in 9 patients (81.8%). Mean overall survival was 13.4 (SD 16.2) months. Spinal expansion duroplasty prior to radiotherapy is a previously undescribed concept. Despite neoadjuvant radiation, no wound breakdown or CSF fistula occurred. In unresectable intramedullary tumors and metastases, spinal expansion duroplasty seems to be a safe procedure with the potential to prevent neurological decline due to radiation-induced cord swelling.

Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors.

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.

Short-term neuropathological aspects of in vivo suicide gene transfer to the F98 rat glioblastoma using liposomal and viral vectors.

To date, only few preclinical protocols on liposomal suicide gene transfer in tumors have been published, none of which directly compared viral to liposomal vectors in terms of immunoreactivity and efficacy. We thus studied the neuropathological alterations in 80 rats being treated for glioblastoma using liposomal and, for comparison, adenoviral and retroviral suicide gene transfer approaches to identify vector-associated efficacy and toxicity for further clinical studies. 62 rats served as controls. F98 tumors were established in Fisher rats and transfected in vivo with the thymidine kinase gene of herpes simplex virus (HSVtk) by a single intratumoral application and an implanted intratumoral continuous delivery system. Three days later ganciclovir was given intraperitoneally for 14 days. The animals were sacrificed 17 days post completed gene transfer. Brains were examined histologically and immunohistochemically using markers for immunocompetent cells. Ten animals showed complete tumor regression; they all belonged to the liposomal and adenoviral groups. In 6 of 10 experimental groups considerable numbers of lymphocytes along the margins of the regression cavities could be observed. Control animals of the liposomal and adenoviral groups showed only little lymphocytic infiltration, underlining the minimal immunogenicity of these carriers. In contrast, the retroviral control group featured a high lymphocyte infiltration. In summary, this study indicates that, in terms of both efficacy and immunoreaction, liposomes are as appropriate as adenoviruses in the treatment of rat glial tumors using suicide gene transfer strategies.

p53 mutation and protein alteration in 50 gliomas. Retrospective study by DNA-sequencing techniques and immunohistochemistry.

Alterations of the p53 protein, which is a 53 kD phosphoprotein and gene product of the p53 gene, has been found to play a major role in the genesis of a variety of human malignancies including tumors of the central nervous system. We investigated 50 tumor specimens from primary central nervous system neoplasms. Tissue samples were screened for mutations by the single-strand conformation polymorphism method and detected mutations were sequenced. All tissue specimens were stained immunohistochemically for p53 protein, which when altered accumulates in the nucleus due to prolonged half-life. Mutations were found in six cases, including one pilocytic astrocytoma World Health Organization (WHO) grade I, two astrocytomas WHO grade II, two anaplastic astrocytomas WHO grade III, and one primitive neuroectodermal tumor (PNET). In terms of relative frequency mutations were found mostly in the group of anaplastic astrocytomas WHO grade III. Interestingly, no mutations were found in the group of investigated glioblastomas. P53 immunopositivity did not correlated with the mutations found, whereas the staining index was significantly higher in the cases with detected mutations than in those without. When p53 alterations is seen as an indicator for different pathogenic pathways in glioma formation, this study gives evidence for a difference between anaplastic astrocytoma and glioblastoma. However, since there was a great overlap in p53 immunopositivity and p53 mutation in tumors of different WHO grades and entities, it seems that p53 will not act as a marker molecule neither for tumor entities nor for tumor malignancy.