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Christian A. Mueller, Hermann J. Schluesener, Sabine Conrad, Torsten Pietsch and Jan M. Schwab

Object

Spinal cord injury (SCI) elicits a strong inflammatory response that readily participates in lipid oxygenation, edema formation, apoptotic cell death, and tissue remodeling. Because cytokines determine the postinjury inflammatory milieu, the authors analyzed the expression of the immunomodulatory chemokine interleukin-16 (IL-16) after SCI.

Methods

The authors detected a highly significant, persistent, lesional accumulation of parenchymal IL-16+ microglia/macrophages, which reached a maximal level 3 days postinjury compared with control rats. The majority of cells that demonstrated positive labeling for IL-16 also had positive labeling for ED1 (> 70%) and OX-8/CD8; these cells exhibited the morphological hallmarks of activated microglia/macrophages and pronounced MHC Class II expression. In contrast to IL-16+ED1+ cells, IL-16+ microglia/macrophages that coexpressed OX-8 were exclusively seen in the pannecrotic lesion core. In addition, clustering of IL-16+ cells was observed in perivascular Virchow–Robin-like spaces in areas of the primary injury (lesion core) and in immediately adjacent areas of secondary injury. Furthermore, on Day 3 postinjury, IL-16+ microglia/macrophages were frequently observed in a perineuronal position.

Conclusions

The early lesional accumulation of IL-16+ microglia/macrophages suggests a role for IL-16 in the early postinjury immune response such as recruitment and activation of immune cells, leading to microvessel clustering and secondary damage progression.

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Christian A. Mueller, Sabine Conrad, Hermann J. Schluesener, Torsten Pietsch and Jan M. Schwab

Object.

Spinal cord injury (SCI) induces the disruption of neural and vascular structures. In contrast to the emerging knowledge of mechanisms regulating the onset of the postinjury angiogenic response, little is known about counterregulatory signals.

Methods.

Using immunohistochemical methods, the authors investigated the expression of the endogenous angiogenic inhibitor endostatin/collagen XVIII during the tissue remodeling response to SCI.

Results.

After SCI, endostatin/collagen XVIII+ cells accumulated at the lesion site, in pannecrotic regions (especially in areas of cavity formation), at the lesion margin/areas of ongoing secondary damage, and in perivascular Virchow–Robin spaces. In remote areas (> 0.75 cm from the epicenter) a more modest accumulation of endostatin/collagen XVIII+ cells was observed, especially in areas of pronounced Wallerian degeneration. The numbers of endostatin/collagen XVIII+ cells reached their maximum on Day 7 after SCI. The cell numbers remained elevated in both, the lesion and remote regions, compared with control spinal cords for 4 weeks afterwards. In addition to being predominantly confined to ED1+-activated microglia/macrophages within the pannecrotic lesion core, endostatin/collagen XVIII expression was frequently detected by the endothelium/vessel walls. Numbers of lesional endostatin/collagen XVIII+ endothelium/vessel walls were found to increase early by Day 1 postinjury, reaching their maximum on Day 3 and declining subsequently to enhanced (above control) levels 30 days after SCI.

Conclusions.

The authors detected that in comparison to the early expression of neoangiogenic factors, there was a postponed lesional expression of the antiangiogenic endostatin/collagen XVIII. Furthermore, the expression of endostatin/collagen XVIII was localized to areas of neovascular pruning and retraction (cavity formation). The expression of endostatin/collagen XVIII by macrophages in a “late” activated phagocytic mode suggests that this factor plays a role in counteracting the preceding “early” neoangiogenic response after SCI.

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Alexandru C. Stan, Mohammad N. Nemati, Torsten Pietsch, Gerhard F. Walter and Hermann Dietz

✓ The effectiveness of in vivo suppression of neovascularization and growth of malignant glial tumors by in situ administration of an antibody directed against basic fibroblast growth factor (bFGF), a strong mitogen for cells of mesodermal origin, was tested. One hundred fifty congenitally athymic nude rats (Han rnu/rnu) were implanted intracerebrally with U-87MG tumor cells, known constitutive producers of bFGF. The animals were randomly assigned to six groups of 25 animals each. Animals were treated by in situ application of saline (Group F), control antibody (Group D), or polyclonal antibFGF antibody (Group B). In additional groups a putative effect on tumor growth caused by the treatment application device itself (between growth control Groups A and E), and the effect of heat-inactivated tumor cells (negative control Group C) were tested. After 3 weeks of treatment, tumor progression and degree of neovascularization were morphometrically recorded. In the untreated Groups A and E massive tumor growth was recorded, consisting of 19.9% ± 0.4% and 27.1% ± 0.5%, respectively, of the total brain cross-sectional area. In Group C, no tumor growth occurred. In control Groups D and F tumor progression consisted of 18.6% ± 0.4% and 18.5% ± 0.4%, respectively, of the total brain crosssectional area; whereas in the anti-bFGF treated Group B, significantly smaller tumor masses measuring 7.2% ± 0.1% were recorded. New blood vessels were located both peritumorally and intratumorally and defined as numerical density and area fraction (number/area and area/area). Significantly more new blood vessels were found in Groups A, D, E, and F, ranging from 41,380/mm2 ± 464/mm2 to 53,442/mm2 ± 150/mm2 peritumorally and 51,846/mm2 ± 495/mm2 to 64,660/mm2 ± 183/mm2 intratumorally than in the anti-bFGF treated Group B, which numbered 8220/mm2 ± 225/mm2 peritumorally and 16,554/mm2 ± 236/mm2 intratumorally. The authors conclude that treatment with anti-bFGF antibody is effective in inhibiting tumor-induced angiogenesis and correlated tumor progression. However, owing to the character of the experimental system used, one cannot exclude the possibility that application of the specific anti-bFGF antibody also counteracts device-induced neovascularization. The authors suggest that combined surgical excision and adjuvant immunotherapy of tumors such as glioblastoma and other malignant brain tumors that express bFGF might prevent tumor recurrence.

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Hans-Juergen Reulen, Gabriele Poepperl, Claudia Goetz, Franz Joseph Gildehaus, Michael Schmidt, Klaus Tatsch, Torsten Pietsch, Theo Kraus and Walter Rachinger

OBJECT

The aim in this study was to present long-term results regarding overall survival (OS), adverse effects, and toxicity following fractionated intracavitary radioimmunotherapy (RIT) with iodine-131− or yttrium-90−labeled anti-tenascin monoclonal antibody (131I-mAB or 90Y-mAB) for the treatment of patients with malignant glioma.

METHODS

In 55 patients (15 patients with WHO Grade III anaplastic astrocytoma [AA] and 40 patients with WHO Grade IV glioblastoma multiforme [GBM]) following tumor resection and conventional radiotherapy, radioimmunoconjugate was introduced into the postoperative resection cavity. Patients received 5 cycles of 90Y-mAB (Group A, average dose 18 mCi/cycle), 5 cycles of 131I-mAB (Group B, average dose 30 mCi/cycle), or 3 cycles of 131I-mAB (Group C, 50, 40, and 30 mCi).

RESULTS

Median OS of patients with AA was 77.2 months (95% CI 30.8 to > 120). Five AA patients (33%) are currently alive, with a median observation time of 162.2 months. Median OS of all 40 patients with GBM was 18.9 months (95% CI 15.8–25.3), and median OS was 25.3 months (95% CI18–30) forthose patients treated with the 131I-mAB. Three GBM patients are currently alive. One-, 2-, and 3-year survival probabilities were 100%, 93.3%, and 66.7%, respectively, for AA patients and 82.5%, 42.5%, and 15.9%, respectively, for GBM patients. Restratification of GBM patients by recursive partitioning analysis (RPA) Classes III, IV, and V produced median OSs of 31.1, 18.9, and 14.5 months, respectively (p = 0.004), which was higher than expected. Multivariate analysis confirmed the role of RPA class, age, and treatment in predicting survival. No Grade 3 or 4 hematological, nephrologic, or hepatic toxic effects were observed; 4 patients developed Grade 3 neurological deficits. Radiological signs of radionecrosis were observed in 6 patients, who were all responding well to steroids.

CONCLUSIONS

Median OS of GBM and AA patients treated with 131I-mABs reached 25.3 and 77.2 months, respectively, thus markedly exceeding that of historical controls. Adverse events remained well controllable with the fractionated dosage regimen.

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Carsten Friedrich, Monika Warmuth-Metz, André O. von Bueren, Johannes Nowak, Brigitte Bison, Katja von Hoff, Torsten Pietsch, Rolf D. Kortmann and Stefan Rutkowski

OBJECT

Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) arising in the brainstem are extremely rare, and knowledge about them is limited. The few existing case series report fatal outcomes. The purpose of this study was to analyze clinical characteristics of and outcome for brainstem CNS-PNET patients treated according to the consecutive, population-based HIT studies covering a 19-year time period.

METHODS

Between September 1992 and November 2011, 6 eligible children with histologically proven brainstem CNS-PNET not otherwise specified and 2 children with brainstem ependymoblastomas (3, partial resection; 3, subtotal resection; 2, biopsy), median age 3.3 years (range 1.2–10.6 years), were treated according to consecutive multimodal HIT protocols for CNS-PNET/medulloblastoma. Postoperative treatment was according to maintenance chemotherapy protocols (3, craniospinal irradiation [CSI] followed by maintenance chemotherapy), sandwich chemotherapy protocols (2, neoadjuvant chemotherapy, CSI, maintenance chemotherapy), or a therapy protocol for children younger than 4 years (3, postoperative chemotherapy followed by CSI).

RESULTS

The median duration of prediagnostic symptoms, predominantly cranial nerve deficits (n = 7), pyramidal tract signs (n = 5), or ataxia (n = 5), was 5 weeks (range 1–13 weeks). The tumors were all located in the pons. Most involved more than half of the pontine axial diameter and were sharply marginated. All patients had postoperative residual disease, including metastasis in 1 case. With 1 exception all tumors progressed early during treatment within 3.9 months (range 2.5–10.4 months), leading to a 1-year event-free survival rate (± standard error) of 13% ± 12%. After progression, patients succumbed early to their disease resulting in a 1-year overall survival rate of 25% ± 15%. The only surviving patient had a partially resected CNS-PNET, received a sandwich chemotherapy protocol, and is without disease progression 14 months after diagnosis.

CONCLUSIONS

CNS-PNET is a rare but important differential diagnosis in childhood brainstem tumors. So far, efficient therapies are lacking. The sampling of tumor material for improved biological understanding and identification of new therapeutic targets is important.

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Martin Benesch, Daniela Weber-Mzell, Nicolas U. Gerber, Katja von Hoff, Frank Deinlein, Jürgen Krauss, Monika Warmuth-Metz, Rolf-Dieter Kortmann, Torsten Pietsch, Pablo Hernáiz Driever, Franz Quehenberger, Christian Urban and Stefan Rutkowski

Object

Reports on spinal cord ependymoma in children are rare. The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000.

Methods

Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified. Four patients had neurofibromatosis Type 2.

Results

With a median follow-up of 4.2 years (range 0.48–15 years), 28 patients (96.6%) were alive. Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy. One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression. Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR. Three additional patients were treated adjuvantly following progression. Estimated progression-free survival and overall survival rates at 5 years were 72.3% (95% CI 50%–86%) and 100%, respectively. Progression-free survival at 5 years is 84.4% (95% CI 50%–96%) for patients following GTR compared with 57.1% (95% CI 25%–69%) for patients who achieved a less than GTR (p = 0.088, log-rank test). A high relapse incidence (4 of 6) was observed among patients with myxopapillary ependymoma.

Conclusions

Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques. Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade. The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.