Radiomics and visual analysis for predicting success of transplantation of heterotopic glioblastoma in mice with MRI.

BACKGROUND: Quantifying tumor growth and treatment response noninvasively poses a challenge to all experimental tumor models. The aim of our study was, to assess the value of quantitative and visual examination and radiomic feature analysis of high-resolution MR images of heterotopic glioblastoma xenografts in mice to determine tumor cell proliferation (TCP). METHODS: Human glioblastoma cells were injected subcutaneously into both flanks of immunodeficient mice and followed up on a 3 T MR scanner. Volumes and signal intensities were calculated. Visual assessment of the internal tumor structure was based on a scoring system. Radiomic feature analysis was performed using MaZda software. The results were correlated with histopathology and immunochemistry. RESULTS: 21 tumors in 14 animals were analyzed. The volumes of xenografts with high TCP (H-TCP) increased, whereas those with low TCP (L-TCP) or no TCP (N-TCP) continued to decrease over time (p < 0.05). A low intensity rim (rim sign) on unenhanced T1-weighted images provided the highest diagnostic accuracy at visual analysis for assessing H-TCP (p < 0.05). Applying radiomic feature analysis, wavelet transform parameters were best for distinguishing between H-TCP and L-TCP / N-TCP (p < 0.05). CONCLUSION: Visual and radiomic feature analysis of the internal structure of heterotopically implanted glioblastomas provide reproducible and quantifiable results to predict the success of transplantation.

Effects of Tetrahydrolipstatin on Glioblastoma in Mice: MRI-Based Morphologic and Texture Analysis Correlated with Histopathology and Immunochemistry Findings-A Pilot Study.

BACKGROUND: This study aimed to investigate the effects of tetrahydrolipstatin (orlistat) on heterotopic glioblastoma in mice by applying MRI and correlating the results with histopathology and immunochemistry. METHODS: Human glioblastoma cells were injected subcutaneously into the groins of immunodeficient mice. After tumor growth of >150 mm3, the animals were assigned into a treatment group (n = 6), which received daily intraperitoneal injections of orlistat, and a control group (n = 7). MRI was performed at the time of randomization and before euthanizing the animals. Tumor volumes were calculated, and signal intensities were analyzed. The internal tumor structure was evaluated visually and with texture analysis. Western blotting and protein expression analysis were performed. RESULTS: At histology, all tumors showed high mitotic and proliferative activity (Ki67 ≥ 10%). Reduced fatty acid synthetase expression was measured in the orlistat group (p < 0.05). Based on the results of morphologic MRI-based analysis, tumor growth remained concentric in the control group and changed to eccentric in the treatment group (p < 0.05). The largest area under the receiver operating curve of the predictors derived from the texture analysis of T2w images was for wavelet transform parameters WavEnHL_s3 and WavEnLH_s4 at 0.96 and 1.00, respectively. CONCLUSIONS: Orlistat showed effects on heterotopically implanted glioblastoma multiforme in MRI studies of mice based on morphologic and texture analysis.

Effects of effective stereotactic radiosurgery for brain metastases on the adjacent brain parenchyma.

BACKGROUND: To evaluate whether functional and metabolic MRI can detect radiation-induced alterations in the adjacent areas after effective stereotactic radiosurgery (SRS) for brain metastases. If confirmed, these techniques may be suited for monitoring the timely stratification of patients for neuroprotective treatments after irradiation. METHODS: Inclusion criteria were complete response, partial response, or stable disease on routine follow-up MR-scans. Multiparametric 3T-MRI was performed with diffusion-weighted imaging, dynamic susceptibility perfusion-weighted imaging, and two-dimensional proton MR-spectroscopy. Parameters were measured in the SRS-treated target and in the adjacent parenchyma up to both 0.75 cm and 1.5 cm from the target border. RESULTS: Nineteen lesions in sixteen consecutive patients met the inclusion criteria. The median follow-up time was 39 months (range, 10-142) with 41 multiparametric MR-examinations in total. We found low values of N-acetyl-aspartate up to 1.5 cm from the target borders of SRS (P = 0.043) associated with high values of choline (P = 0.004) at the end of the observation period. Lactate levels in the adjacent tissue declined over time, whereas continuously high apparent-diffusion-coefficient values were noted (P < 0.001). CONCLUSION: Multiparametric MRI can depict radiobiological effects and their time course at a distance from the effectively treated site after SRS for brain metastases, even if conventional MRI findings are inconspicuous.

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.

Incidental findings in computed tomographic angiography for planning percutaneous aortic valve replacement: advanced age, increased cancer prevalence?

BACKGROUND: Increased age is linked with a higher cancer risk according to model calculations. Patients with severe atherosclerotic aortic stenosis are of old age, therefore, a high incidence of malignancies should be found. PURPOSE: To evaluate the prevalence of clinically significant and potentially malignant incidental findings at computed tomographic angiography (CTA) performed in patients with severe aortic stenosis being assessed as to their suitability for transcatheter aortic valve replacement (TAVR). MATERIAL AND METHODS: Between August 2008 and April 2010, CTA of the thoraco-abdominal aorta and the pelvic arterial vessels was performed in 131 patients. There were 62 women (47%) and 69 men (53%); the mean age was 81.6 years (range, 64-91 years). Incidental findings were recorded and categorized as potentially malignant, clinically significant, and clinically insignificant. Clinically significant findings were defined as those requiring immediate therapy, intervention or imaging, or follow-up examination. RESULTS: Of the 131 study patients, 31 (23.7%) presented significant extravascular incidental findings, 19 (14.5%) in the thorax, and 12 (9.2%) in the abdomen. Five lesions (3.8%) were considered potentially malignant, three of them (2.3%) were new and highly suspicious for malignancies (two renal cell carcinomas and one hepatocellular carcinoma). In two patients (1.5%) mediastinal lymphadenopathy was found (recurrent malignant lymphoma und new metastases from known bladder cancer). CONCLUSION: The prevalence of highly suspicious malignant incidental findings in patients undergoing TAVR is 3.8% with an average age of 81.6 years which is not high compared to prevalence in the literature dealing with patients aged <70 years.

The interior structure of breast microcalcifications assessed with micro computed tomography.

BACKGROUND: Morphology microcalcification descriptors help stratify the risk of breast malignancy. Micro CT is feasible for visualization of the fine-structure of tissues and may be suitible for high resolution microcalcification analysis. PURPOSE: To analyze the interior structure of microcalcifications using a micro CT imaging system. MATERIAL AND METHODS: Core needle breast biopsy specimens from 16 women with clustered microcalcifications were examined with micro CT. The samples measured between 0.8 to 1.2 mm in diameter. Micro CT scans with an isotropic voxel size of 8.4 µm were obtained to generate two- and three-dimensional images of the microcalcifications. The number of microcalcifications were counted on the magnified specimen radiogram and on micro CT. Attenuation values of microcalcifications were measured by drawing a region of interest (ROI) in the center of the microcalcifications. Two blinded observers assessed the morphology and the interior structure of microcalcifications. RESULTS: Five patients had benign and 11 patients had malignant breast lesions. On micro CT, microcalcifications of benign tissue showed a coarse lamellar or trabecular interior structure, whereas microcalcifications of breast cancer tissue showed a more uniform granular interior structure. There was no correlation between attenuation values of benign compared with malignant microcalcifications. CONCLUSION: On micro CT, an interior structure of microcalcifications is detectable. Benign and malignant microcalcifications display different patterns of interior structure.

Fine structure of breast tissue on micro computed tomography a feasibility study.

RATIONALE AND OBJECTIVES: To evaluate the feasibility of micro computed tomography (CT) to assess the fine structure of breast tissue. METHODS AND MATERIALS: Breast core needle biopsy specimens (0.8 to 1.2 mm diameter) from fifteen women with clustered microcalcifications were examined using micro CT with isotropic voxels of 8.4 µm. Reconstructed two- and three-dimensional images were compared with the corresponding histological slices. Gray-scale measurements were performed in adipose tissue, fibroglandular tissue, fibrous tissue, microcalcifications, and tumor. The Tukey-Kramer method was applied to test the statistically significant differences between gray-scale attenuation values of breast tissue components. RESULTS: Soft-tissue architecture appearance at micro CT closely approximated that obtained by light microscopy at low power field. The Tukey-Kramer method revealed statistically significant differences for attenuation values for all combinations of breast tissue components with the exception of fibroglandular tissue versus fibrous tissue. CONCLUSIONS: Micro CT is feasible for the differentiation of breast tissue components from core needle specimens.

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

BACKGROUND: 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. PROCEDURE: The Fertigkeitenskala Münster-Heidelberg (FMH) is a 56-item quantitative measure of health status. The number of yes answers is transformed to age-dependent percentiles. Physicians were also asked the patients' health status by their own judgment on a 1-5 scale: normal, mild handicap, age-normal activity severely reduced but patient not in bed, in bed, and in ICU. RESULTS: Assessments were available from 50 of 97 eligible patients. For 22 patients both questionnaire and the physicians score obtained. At the beginning of the treatment, only 5 patients scored over 40 FMH%, and 4 of these survived. Of 16 patients who initially scored less than 40 FMH%, 15 died. During later assessments, most FMH measures became gradually worse. FMH scores improved in three patients. The physician's judgment was documented at diagnosis and during treatment (n = 50). Per physician, 22% of the patients were normal before chemotherapy, decreasing to 16% in the middle of the protocol. At diagnosis only 16% of patients had severely reduced activity, which increased to 30.6% in the middle of the protocol. The FMH% correlated well with the physicians' judgments (P < 0.005). CONCLUSION: The FMH scale is easily obtained and provides a valid assessment of health status. Patients with poor performance at diagnosis had a poorer prognosis.

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

BACKGROUND: 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). PROCEDURE: Twenty-four patients were included retrospectively. Methylation specific PCR (MSP), calibrated combined bisulfite restriction analysis (COBRA), and immunohistochemistry (IHC) were applied. Survival analyses were performed by Kaplan-Meier and Cox proportional-hazards models. RESULTS: MSP demonstrated DNA methylation in 77%. Patients with a methylated MGMT promoter had a sixfold longer median EFS (P = 0.015; 5.5 months vs. 0.9 months). Considering the results of calibrated COBRA, MGMT methylation was again associated with an elevated EFS (P = 0.05; 10.2 months vs. 2.6 months) and OS (P = 0.06; 18.7 months vs. 7.2 months) only if methylation was >14%. No difference in EFS and OS at all was noted between unmethylated and tumors methylated at low level (n = 9). Twenty-two tumors were positive by IHC, 10 showed low MGMT expression (IHC score 0-4). We did not detect any difference in EFS and OS between moderate/high-expressing tumors (IHC score 6-12) and those with low or no expression (IHC score 0-4). CONCLUSION: DNA methylation, but not protein expression of MGMT was associated with an increased median EFS and OS of children with relapsed HGG. MGMT methylation status warrants prospective evaluation as a stratification marker for children with HGG.

Contrast enhanced MR angiography with parallel imaging in the early period after renal transplantation.

PURPOSE: To evaluate renal allograft vessels in the early period after kidney transplantation with three-dimensional (3D) contrast-enhanced MR angiography (3D CE MRA) using a parallel imaging technique. MATERIALS AND METHODS: Sixty-three consecutive patients were examined with 3D CE MRA and integrated SENSE technique (Sensitivity Encoding) 2 to 21 days after renal transplantation. MR angiography studies were analyzed for the presence of arterial stenosis. The degree of renal transplant artery stenosis was graded qualitatively as <50% = mild, 50-70% = moderate, 70-99% = severe, and occlusion. Four patients (6.3%) with moderate (n = 1) or severe (n = 3) arterial stenoses on CE MRA underwent selective intra-arterial digital subtraction angiography. In two patients, selective intravenous digital subtraction angiography (DSA) was performed. RESULTS: Twenty-seven (42.9%) of the 63 patients had normal CE MR angiograms, 29 (46%) showed mild, 3 patients (4.8%) moderate, and 4 patients (6.3%) severe stenoses of the donor artery. In three patients, the severe stenosis of the graft artery was confirmed by surgery or intra-arterial DSA. One patient with suspicion of severe arterial stenosis on MRA had moderate vessel narrowing on DSA. Twelve months after kidney transplantation, serum creatinine levels were not significantly different in patients with mild and moderate stenoses from those without (P > 0.19) but significantly different from those with severe stenoses (P < 0.05). CONCLUSION: The incidence of mild and moderate vessel narrowing at the arterial anastomosis is unexpectedly high in the early period after kidney transplantation and is most likely due to surgery-related tissue edema.

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.

Subpopulations of malignant gliomas in pediatric patients: analysis of the HIT-GBM database.

Pediatric malignant gliomas represent a heterogeneous group of tumors. This publication reviews data from the first three HIT-GBM protocols. One important question is whether it makes sense to include both histologically confirmed high-grade glial tumors (HGG), and radiologically confirmed diffuse intrinsic pontine gliomas in a single study. Three-hundred-and ten patients (173 male, median age 10.0 years) were enrolled. Tumor locations were cerebral hemispheres: 80, basal ganglia: 38, pons: 134, non-pontine brain stem: 14, cerebellum: 14, spinal: 8, and overlapping areas: 22. Surgical resection was complete in 49, subtotal in 35, partial in 58, biopsy in 99, and no surgery in 69 cases. One-hundred-and twenty-three cases corresponded to WHO grade IV, 101 to III, and 15 to I/II. Two-hundred-and twenty-eight patients could be evaluated for response: CR: 8, PR: 32, SD: 116, and PD: 72. Median overall survival time was 1.03 years, and median event free survival was 0.54 years. Five year OS-rate was 10.28 +/- 2.1%. In the total database, tumor location, grading, and extent of surgical resection were prognostic factors, but the relevance differed in location subgroups with no relevance for sex, histological grading or extend of surgical resection in pontine tumors. Possible prognostic factors were not distributed homogeneously. Pontine tumors differed from cerebral hemisphere tumors concerning the frequency of previous diseases, the age at diagnosis (median age pons 7.9 years versus cerebral hemispheres 11.4 years), and the frequency of WHO grade III versus Grade IV (III:IV = 1.6 for pons, and 0.7 for cerebral hemispheres). We conclude that the biology of pontine glioma differs significantly from other HGG, and clinical studies should be separate with different endpoints.

Pegylated-liposomal doxorubicin and oral topotecan in eight children with relapsed high-grade malignant brain tumors.

BACKGROUND: The combination of topoisomerase I and II chemotherapeutic agents has shown promising preclinical synergistic effects in the treatment of high-grade malignant brain tumors such as high-grade gliomas and choroid plexus carcinomas. To confirm the effectiveness of this treatment combination and determine its possible toxicity, we conducted a retrospective review of the charts of children who received the therapy. METHODS: Patients with relapsed malignant brain tumors who were given an individualized treatment of pegylated (PEG)-liposomal doxorubicin and topotecan were included in our study. PEG-liposomal doxorubicin was given intravenously at a dosage of 30-40 mg/m(2) over 4 h once every 4 weeks. Additionally, an intravenous formulation of topotecan was given orally twice daily and was increased on an individual basis from a starting dosage of 0.3 mg/m(2) per application to a total daily dosage of 0.6 mg/m(2). RESULTS: Eight patients were included. The main toxicity (NCI-CTC) after three cycles of the combination therapy was grade IV hematotoxicity (n = 3); grade III hematotoxicity (n = 2), grade III stomatitis (n = 1), grade III infection (n = 2), grade III diarrhea (n = 1); and grade II dermatitis (n = 1). In four patients, stable disease was achieved for 9, 23, more than 24, and more than 48 weeks, respectively. CONCLUSION: The schedule of PEG-liposomal doxorubicin with 30-40 mg/m(2) every 4 weeks in combination with oral topotecan resulted in tumor response, but the toxicity was high. An individualized increasing dose of PEG-liposomal doxorubicin 10-20 mg/m(2) every two weeks is now recommended.

Cerebral MRI lesions and anti-tumor necrosis factor-alpha therapy.

We discuss two cases receiving different anti-tumornecrosis-factor alpha antagonists (anti-TNF-alpha); one for psoriatic arthritis (PA) and the other for ankylosing spondylitis (AS). Due to neurological symptoms cerebral magnetic resonance imaging (MRI) was performed and cerebral lesions were detected. Our interpretations of these cerebral lesions and the resulting diagnostic and therapeutic consequences are presented in regard of data published in the medical literature.

Improved survival after gross total resection of malignant gliomas in pediatric patients from the HIT-GBM studies.

The present study was performed to investigate the prognostic impact of tumor resection on survival in children and adolescents with malignant gliomas. From the HIT-GBM data base of the Gesellschaft für Paediatrische Onkologie und Haematologie (GPOH), 85 pediatric patients with malignant non-pontine gliomas were analyzed. Histological diagnosis and extent of tumor resection had been confirmed by central neuropathological review and post-surgical imaging. The extent of tumor resection represented the most prominent prognostic factor for overall (OS) and event-free survival (EFS) in univariate and Cox regression analyses. Four-year survival after gross total tumor resection was 48.0 +/- 12.0% (OS) and 14.1 +/- 8.9% (EFS), after non-total resection 13.2 +/- 6.1% and 2.9 +/- 2.8%, respectively. From several clinical parameters, only histological grading displayed a similar statistical significance in Cox regression analysis. In conclusion, gross total tumor resection improves survival in pediatric patients with malignant gliomas and should always be attempted when possible.

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.

SET-mediated promoter hypoacetylation is a prerequisite for coactivation of the estrogen-responsive pS2 gene by PRMT1.

Induction of transcription requires an ordered recruitment of coregulators and specific combinations of histone modifications at the promoter. Occurrence of histone H4 arginine (Arg) 3 methylation by protein arginine methyltransferase 1 (PRMT1) represents an early promoter event in ER (estrogen receptor)-regulated gene activation. However, its in vivo significance in ER signaling and the prerequisites for PRMT1 recruitment to promoters have not been established yet. We show here that endogenous PRMT1 is a crucial and non-redundant coactivator of ER-mediated pS2 gene induction in MCF7 cells. By investigating promoter requirements for PRMT1 recruitment we find that the patient SE translocation (SET) protein, which was reported to protect histone tails from acetylation, associates with the uninduced pS2 gene promoter and dissociates early upon estrogen treatment. Knockdown of SET or trichostatin A (TSA) treatment causes premature acetylation of H4 and abrogation of H4 Arg3 methylation at the pS2 gene promoter resulting in diminished transcriptional induction. Thus, SET prevents promoter acetylation and is a prerequisite for the initial acetylation-sensitive steps of pS2 gene activation, namely PRMT1 function. Similar to pS2 we identify lactoferrin as a PRMT1-dependent and TSA-sensitive ER target gene. In contrast, we find that the C3 gene, another ER target, is activated in a PRMT1-independent manner and that SET is involved in C3 gene repression. These findings establish the existence of PRMT1-dependent and -independent ER target genes and show that proteins guarding promoter hypoacetylation, like SET, execute a key function in the coactivation process by PRMT1.

Maintenance treatment with interferon-gamma and low-dose cyclophosphamide for pediatric high-grade glioma.

BACKGROUND: The prognosis of high-grade glioma in children is poor. PURPOSE: Interferon-gamma may increase the immune surveillance of glioma cells. Earlier clinical evidence had shown that low dose cyclophosphamide (CPM) increased immune response. METHODS: After induction treatment with simultaneous radiation and chemotherapy, patients were treated with individually increasing interferon-gamma (IFN-gamma) doses starting from 25 microg/m2/d s.c. increasing up to a maximum of 175 microg/m2/d within 7 weeks. Cyclophosphamide was given at 300 mg/m2 i.v. every 21 days. Forty pediatric glioma patients were enrolled (median age: 8.5 year, male: n = 22). Tumor locations included cerebral cortex (n = 8), basal ganglia (n = 4), brainstem (n = 24), cerebellum (n = 3), spinal cord (n = 1). Histologies were GBM (n = 14), AA (n = 14), LGG (n = 2, diffuse intrinsic pontine glioma). There was grade IV toxicity for thrombocytopenia (10%) and leucopenia (2.5%), grade III toxicity for central nervous (2.5%) and hepatic (5%) side effects, no toxic death. The observation time of the six surviving patients was: 1.2, 1.9, 4.2, 4.4, 4.6 and 4.7 years respectively. The median overall survival (1 year) was not significantly different from a historical control group (0.8 years). The survival of pontine gliomas appeared even inferior when compared to the previous protocol (n.s.). CONCLUSION: Maintenance treatment with IFN-gamma and low dose CPM has no sufficient beneficial effect for the treatment of high-grade glioma.

Treatment options in childhood pontine gliomas.

BACKGROUND: Pontine gliomas are the subgroup of brainstem gliomas with the worst prognosis. Controversial treatment approaches are discussed. PATIENTS AND METHODS: Data of children with pontine gliomas treated in different prospective multi-center studies who were registered in the HIT-GBM database were pooled and analyzed addressing prognostic factors and the relevance of intensive treatment using contingency tables, Kaplan-Meier curves and Cox regression analyses. RESULTS: From 1983 to 2001, 153 patients (74 males, 79 females, mean age: 8.1 years) with pontine gliomas were registered. Twenty-one tumors were low-grade and 60 were high-grade gliomas (72 undefined histology: 67 no surgery, 5 incomplete data). Sixteen tumors were partially resected, and 125 were irradiated. Ninety children received chemotherapy according to the "HIT-GBM" protocols ("Hirntumor-Glioblastoma multiforme"). The one-year overall survival rate (1YOS) of all patients with pontine glioma was 39.9+/-4.3%. None of the surviving patients had an observation time longer than 3.9 years. Favorable prognostic factors seemed to be age younger than 4 years, low-grade histology and smaller tumor. All three major treatment modalities including resection, irradiation and chemotherapy had prognostic relevance in univariable analysis. Chemotherapy remained beneficial, even if the analysis was restricted to the subgroup of irradiated tumors (1YOS 45.8+/-5.4% vs. 34.4+/-13.5%, P=0.030). CONCLUSION: Irradiation is an effective element for the treatment of pontine gliomas. Intensive chemotherapy seems to be important in achieving a better OS.

High-dose methotrexate prior to simultaneous radiochemotherapy in children with malignant high-grade gliomas.

BACKGROUND: Preradiation chemotherapy including methotrexate (MTX) was effective in children with completely resected high-grade gliomas (HGG). The specific role of MTX remains uncertain. PATIENTS AND METHODS: Children with newly diagnosed HGG and diffuse intrinsic pontine gliomas (DIPG) were enrolled. Two cycles of HD-MTX (5 mg/m2) were given prior to simultaneous radiochemotherapy (SRCT). Response was evaluated two weeks after SRCT. RESULTS: Of 26 children (17 males, median age: 10.3 years) tumor grading was WHO IV (n=9), III (n=10), II/I (n=4, DIPG), unknown (n=3, DIPG). Fourteen tumors were resected. III/IV toxicity after SRCT was: 10/19 anemia, 15/19 leukocytopenia, 12/19 thrombocytopenia, 8/18 infection. No IV infection, gastrointestinal, hepatic or dermal toxicity or toxic death was seen. Stable disease or better was seen in 95.3% (CCR:2, CR:1, PR:8, SD:9, PD:1, unknown:5). CONCLUSION: HD-MTX prior to SRCT is well tolerated and feasible. A randomized trial evaluating the effect of HD-MTX on survival is justified.