Ove Peters

Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor.

The SMARCB1 gene status in 50 patients with atypical teratoid rhabdoid tumor and/or malignant rhabdoid tumor recruited to a German registry was prospectively analyzed with FISH and PCR. Altogether we found 40 SMARCB1 mutations in 28 patients. Two patients were positive for SMARCB1 staining at immunochemistry. Germline mutations were identified in 10 of 41 patients with CNS disease, including three large heterozygous deletions, six truncating mutations and one donor splice site mutation. No missense mutation was identified. Analysis of first degree relatives did not detect any carriers. Mutations were distributed over the SMARCB1‐gene without particular clustering. No germline mutation was found in nine patients without CNS disease. Patients with germline mutation had a lower median age at diagnosis in comparison to those without detectable germline mutation (5.5 vs. 13 months, P = 0.001), a higher rate of primary multicentric CNS disease (5/10 vs. 5/36) and synchronous or metachronous mixed CNS and extracranial disease (4/10 vs. 1/36). Two year overall survival was 0% in patients with germline mutation and 48% in those without detectable germline mutation (P < 0.001). Patients with germline mutation of SMARCB1 manifest at an early age and have a very high risk for progression which has to be considered with respect to the outcome of further treatment studies.

Malignant progression in choroid plexus papillomas

OBJECT Malignant progression of choroid plexus papillomas has been occasionally reported, but this issue has not yet been systematically addressed. METHODS Frequency and extent of malignant progression were examined in a retrospective series of 124 primary choroid plexus papillomas using uniform histological criteria. RESULTS After gross-total resection and a mean follow-up period of 59 months, 12 recurrences necessitating neurosurgical intervention had occurred in the 103 cases of choroid plexus papilloma (World Health Organization [WHO] Grade I) and 21 cases of atypical choroid plexus papilloma (WHO Grade II). The proportion of recurring tumors was higher in cases of atypical choroid plexus papilloma than in cases of choroid plexus papilloma (six [29%] of 21 compared with six [6%] of 103, respectively; p < 0.05). In the majority (10 of 12) of the recurrences, there was a close correspondence between the primary tumor and the recurrence with respect to features identified on routine histological examination as well as Ki 67 (MIB-1) proliferation indices (median value 4% for both primary and recurrent tumors; range 0-15% for primary compared with 0-12% for recurrent tumors). However, two patients experienced a transition from a choroid plexus papilloma (WHO Grade I) and an atypical choroid plexus papilloma (WHO Grade II) to choroid plexus carcinomas (WHO Grade III). CONCLUSIONS Recurrent tumor growth after gross-total resection is rare in choroid plexus papillomas, but malignant progression to choroid plexus carcinoma does occur in a small percentage of tumors.

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.

Platelet-Derived Growth Factor Receptor Expression and Activation in Choroid Plexus Tumors

Choroid plexus tumors are intraventricular neoplasms predominantly affecting young children. In contrast to choroid plexus papillomas, choroid plexus carcinomas progress frequently, necessitating the development of adjuvant treatment concepts. Platelet derived growth factor (PDGF) signaling has been shown to support growth in a variety of tumors. The finding of PDGF receptor expression in choroid plexus tumors prompted us to elucidate PDGF receptor activation state using a novel method, in situ proximity ligation assay, on formalin-fixed, paraffin-embedded, archival samples of 19 choroid plexus tumors. As assessed by in situ proximity ligation assay, the proportion of phosphorylated PDGF receptor alpha was low in choroid plexus papillomas and choroid plexus carcinomas, whereas phosphorylated PDGF receptor beta was found to be significantly higher in choroid plexus carcinomas. In the immortalized choroid plexus epithelial cell line Z310 expressing PDGF receptor beta, PDGF-BB exhibited a time- and dose-dependent proliferative response, which was significantly attenuated by imatinib (gleevec). In conclusion, our findings suggest that PDGF receptor beta is functionally involved in the biology of choroid plexus tumors and may represent a molecular target for therapy. In addition, this study demonstrates the feasibility and usefulness of in situ proximity ligation assay for monitoring receptor tyrosine kinase activation in formalin-fixed, paraffin-embedded, archival tissues.

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.

Aberrant MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation in choroid plexus tumors

Aberrant methylation of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene is a predictive marker for the response to chemotherapy with alkylating agents (e.g., temozolomide) in malignant gliomas. Since temozolomide is considered for the treatment of choroid plexus tumors, MGMT promoter methylation status was retrospectively assessed in 36 choroid plexus tumors using methylation specific PCR, combined bisulfite restriction analysis (COBRA), and clone sequencing. By methylation specific PCR, all samples demonstrated a signal for MGMT methylation. COBRA confirmed >10% methylation of CpGs 17 and 31 in 58% of tumors. Clone sequencing of six cases methylated by COBRA confirmed aberrant methylation including a previously recognized enhancer element. In conclusion, MGMT promoter methylation is frequent in choroid plexus tumors and can be quantified using COBRA. Determination of MGMT promoter methylation status might be useful for the stratification of patients for alkylator-based treatments in future clinical trials.

Intratumoral methotrexate kinetics in a patient with intracranial anaplastic ependymoma

Little is known about intratumoral anticancer drug concentration in childhood brain tumors. We were able to measure methotrexate (MTX) tumor concentrations directly in a cystic anaplastic ependymoma. Cyst fluid was obtained by puncture of a subgaleal Rickham reservoir connected to a catheter in the tumor cyst. MTX concentrations were determined by fluorescence polarization immunoassay and compared to serum concentrations. Maximum MTX concentrations in tumor and CSF were found at the end of MTX infusion. Twenty‐four hour after MTX infusion the mean tumor concentration was significantly higher than in the serum indicating MTX retention and accumulation in the tumor cyst. An AUCtumor/AUCserum ratio of 1.95 was obtained. In response to the applied multiagent chemotherapy the clinical condition of our patient improved and the tumor showed partial response on MRI. Cystic ependymomas might benefit from high dose MTX especially because of drug retention in the tumor cyst.