Sabine Wagner

Postoperative Adjuvant Dendritic Cell–Based Immunotherapy in Patients with Relapsed Glioblastoma Multiforme

Purpose: To investigate the therapeutic role of adjuvant vaccination with autologous mature dendritic cells (DC) loaded with tumor lysates derived from autologous, resected glioblastoma multiforme (GBM) at time of relapse. Experimental Design: Fifty-six patients with relapsed GBM (WHO grade IV) were treated with at least three vaccinations. Children and adults were treated similarly in three consecutive cohorts, with progressively shorter vaccination intervals per cohort. Feasibility and toxicity were assessed as well as effect of age, extent of resection, Karnofsky Performance Score, and treatment cohort on the progression-free (PFS) and overall survival (OS) using univariable and multivariable analysis. Results: Since the prevaccine reoperation, the median PFS and OS of the total group was 3 and 9.6 months, respectively, with a 2-year OS of 14.8%. Total resection was a predictor for better PFS both in univariable analysis and after correction for the other covariates. For OS, younger age and total resection were predictors of a better outcome in univariable analysis but not in multivariable analysis. A trend to improved PFS was observed in favor of the faster DC vaccination schedule with tumor lysate boosting. Vaccine-related edema in one patient with gross residual disease before vaccination was the only serious adverse event. Conclusion: Adjuvant DC-based immunotherapy for patients with relapsed GBM is safe and can induce long-term survival. A trend to PFS improvement was shown in the faster vaccination schedule. The importance of age and a minimal residual disease status at the start of the vaccination is underscored.

Combined treatment of pediatric high‐grade glioma with the oncolytic viral strain MTH‐68/H and oral valproic acid

The case of a 12‐year‐old boy with anaplastic astrocytoma of the left thalamus is reported. Postoperative irradiation and chemotherapy could not repress tumor progression; therefore, treatment was undertaken with an oncolytic virus, MTH‐68/H, an attenuated strain of Newcastle disease virus (NDV), and valproic acid (VPA), an antiepileptic drug, which also has antineoplastic properties. This treatment resulted in a far‐reaching regression of the thalamic glioma, but 4 months later a new tumor manifestation, an extension of the thalamic tumor, appeared in the wall of the IVth ventricle, which required a second neurosurgical intervention. Under continuous MTH‐68/H – VPA administration the thalamic tumor remained under control, but the rhombencephalic one progressed relentlessly and led to the fatal outcome. In the final stage, a third tumor manifestation appeared in the left temporal lobe. The possible reasons for the antagonistic behavior of the three manifestations of the same type of glioma to the initially most successful therapy are discussed. The comparative histological study of the thalamic and rhombencephalic tumor manifestations revealed that MTH‐68/H treatment induces, similar to in vitro observations, a massive apoptotic tumor cell decline. In the rhombencephalic tumor, in and around the declining tumor cells, NDV antigen could be demonstrated immunohistochemically, and virus particles have been found in the cytoplasm of tumor cells at electron microscopic investigation. These findings document that the oncolytic effect of MTH‐68/H treatment is the direct consequence of virus presence and replication in the neoplastic cells. This is the first demonstration of NDV constituents in an MTH‐68/H ‐treated glioma.

Secondary dissemination in children with high-grade malignant gliomas and diffuse intrinsic pontine gliomas

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.

MGMT as a potential stratification marker in relapsed high-grade glioma of children: The HIT-GBM experience†

Studies in adults with malignant glioma suggest MGMT methylation as a stratification marker. Similar data for children are sparse. We investigated the impact of MGMT methylation and expression on survival of children with high‐grade glioma (HGG) registered into the German HIT‐GBM database receiving temozolomide (TMZ) as part of their treatment (n = 21 relapsed, n = 4 primary).

Oral topotecan in children with recurrent or progressive high-grade glioma: A Phase I/II study by the German Society for pediatric oncology and hematology

Continuous oral treatment with topotecan may be more effective than the typical 1‐day and 5‐day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high‐grade glioma is quite limited.

LATE RESPONSE TO RADIOCHEMOTHERAPY IN PEDIATRIC GLIOBLASTOMA: Report on Two Patients Treated According to HIT-GBM Protocols

High-grade gliomas in children are rare and the best treatment is undetermined. The German language group study HIT-GBM compares various induction protocols for subsequent patient cohorts. Currently, cisplatinum, etoposide, ifosfamide, and vincristine are given simultaneously with extended-field radiotherapy. Imaging is done 3 weeks after to define treatment response, followed by 6-weekly controls during consolidation with lomustine, vincristine, and prednisone. The authors report on 2 patients with incompletely resected glioblastoma multiforme in which response was lacking 3 weeks after radiochemotherapy but became evident 12 weeks later. This suggests that later time points are required to assess induction protocol response.

Radiation injury versus malignancy after stereotactic radiosurgery for brain metastases: impact of time-dependent changes in lesion morphology on MRI

Background We sought to determine whether radiation-induced injuries could be distinguished from malignancy after stereotactic radiosurgery (SRS) by analyzing time-dependent changes in lesion morphology on sequential MRI for up to 55min. Methods In 31 consecutive patients treated with SRS for brain metastases, the time-dependent changes in lesion morphology were analyzed on MRI 2min, 15min, and 55min after contrast administration and on subtraction images. A simultaneous, matched-pairs approach was used for quantitative region of interest analysis of the area of the lesion. Qualitative analysis comprised the shape of the border, the structure of the interior area, the presence of leptomeningeal enhancement, and feeding vessels. The signal intensity changes of the border and the interior area of the lesions over time were assessed visually. The time-dependent changes in the 2 entities were compared. Results Twenty radiation-induced injuries and 21 malignancies were analyzed. A significant interaction effect between time point and diagnosis (P<.001) was found for the time-dependent changes of the margin of the lesion for 2min to 15min and in signal intensity differences of the rim and interior area as well as of the size of the interior area for up to 55min. All radiation-induced injuries showed a black interior area on the subtraction images for 15min minus 55min, whereas all malignant lesions had white components (P<.001). Conclusions Analysis of time-dependent changes in lesion morphology on sequential MRI for up to 55min is a reliable tool to distinguish radiation-induced injuries from malignancy after SRS.

Measuring performance status in pediatric patients with brain tumors—experience of the HIT-GBM-C protocol†‡

Measuring the quality of life or performance status in pediatric neurooncology has proven a challenge. Here, we report in a treatment protocol for pediatric patients with high‐grade glioma and diffuse intrinsic pontine glioma.