Journal of Neuro-Oncology

We aimed to evaluate the feasibility and tolerability of the newly developed thermotherapy using magnetic nanoparticles on recurrent glioblastoma multiforme. Fourteen patients received 3-dimensional image guided intratumoral injection of aminosilane coated iron oxide nanoparticles. The patients were then exposed to an alternating magnetic field to induce particle heating. The amount of fluid and the spatial distribution of the depots were planned in advance by means of a specially developed treatment planning software following magnetic resonance imaging (MRI). The actually achieved magnetic fluid distribution was measured by computed tomography (CT), which after matching to pre-operative MRI data enables the calculation of the expected heat distribution within the tumor in dependence of the magnetic field strength. Patients received 4–10 (median: 6) thermotherapy treatments following instillation of 0.1–0.7 ml (median: 0.2) of magnetic fluid per ml tumor volume and single fractions (2 Gy) of a radiotherapy series of 16–70 Gy (median: 30). Thermotherapy using magnetic nanoparticles was tolerated well by all patients with minor or no side effects. Median maximum intratumoral temperatures of 44.6°C (42.4–49.5°C) were measured and signs of local tumor control were observed. In conclusion, deep cranial thermotherapy using magnetic nanoparticles can be safely applied on glioblastoma multiforme patients.

This study concerns the use of the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] colorimetric assay to evaluate the chemosensitivity of the C6 rat glioma cell line to a panel of twelve chemotherapeutic agents. In a previous study of in vitro chemosensitivity of human glioma cell lines, the present authors found a range of sensitivities of the respective cell lines to a panel of chemotherapeutic agents [1]. We then devised an experimental strategy to begin an in vivo evaluation of the correlation between in vitro chemosensitivity and clinical response in an in vivo animal model, such as the model employing the C6 rat glioma cell line. As a step towards utilizing the C6 rat glioma in vivo model, we carried out the present study (Part 1) to determine the correspondence between chemosensitivity to human glioma cell lines and the rat C6 glioma cell line. If a correspondence were to be found, this would enable experimental use of the C6 tumor model for in vivo testing of chemotherapeutic agents. As reported in this paper (Part 1), a correspondence was found, suggesting that the C6 rat glioma represents a suitabe model of human glioma for chemotherapeutic studies. This finding served as a basis for proceeding with an in vivo study of chemotherapeutic efficacy which is the subject of a companion report [2].

The impact of multiple primary tumors, in the setting of malignant glioma (MG), has not been heavily explored. We extracted demographics and clinical data from the SEER-18 registry for adult patients with MGs. The cases were separated based on the sequence of MG diagnosis relative to the other primary tumors: Group (A) One primary only or first primary of multiple primaries and Group (B) second primary or subsequent primary tumor. Incidences, frequencies, and glioma-related survivals were analyzed. Group B constituted 12.8% of new MG. The incidences of group B, relative to those of all new MG, range from 0.14 to 0.18. Compared to group A, group B exhibited an older age. Moreover, group B exhibited a higher proportion of females, Caucasians, smaller tumors, non-operative cases, and those receiving radiation (p < 0.05); the proportion with GTR remained comparable. Multiple groupings (oral cavity, digestive system, respiratory system, skin, breast, genital systems, urinary system, lymphoma) exhibited lower glioma-related observed survival (p < 0.05) compared to Group A. An active diagnosis of “leukemia” appears to confer longer glioma-related survival while a history of “breast” or “digestive system” malignancies portends a shorter glioma-related survival. For newly diagnosed MG, a high proportion does have history of extra-CNS primary tumors. Generally, these patients appear to have worse glioma-related observed survival compare to those with malignant glioma as the only primary or the first of multiple primary tumors. Knowledge regarding epidemiology, clinical factors, and observed survival can help guide clinical management/consultation for this subset of patients.

Advantages of computerized assessment of neuropsychological functions include improved standardization and increased reliability of response time variables. Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) is a computerized battery developed for monitoring recovery following mild brain injuries that assesses attention, memory and processing speed. Despite evidence that core areas of deficit among cancer survivors are those assessed by ImPACT, it has not previously been used with this population. Twenty four childhood brain tumor (BT) survivors treated with conformal radiation therapy (mean age = 15.7 ± 1.6; mean age at irradiation = 9.8 ± 2.5), twenty solid tumor (ST) survivors treated without CNS-directed therapy (mean age = 16.2 ± 1.8) and twenty healthy siblings (mean age = 15.1 ± 1.6 years) were administered an age modified version of ImPACT. Additional computerized measures of working memory and recognition memory were administered. Univariate ANOVAs revealed group differences (p < 0.05) on measures of recognition memory, spatial working memory, processing speed and reaction time, with BT survivors performing significantly worse than ST survivors and siblings. Pearson correlation coefficients revealed significant associations between ImPACT memory tasks and computerized forced choice recognition tasks (rs = 0.30−0.33, p < 0.05). Multiple surgical resections, hydrocephalus and CSF shunt placement most consistently predicted worse ImPACT performance using linear mixed models (p < 0.05). The ImPACT test battery demonstrated sensitivity to cognitive late effects experienced by some BT survivors with clinical predictors of performance consistent with the pediatric oncology literature. Correlations with measures of similar constructs provide evidence for convergent validity. Findings offer initial support for the utility of ImPACT for monitoring of cognitive late effects.

This prospective clinical trial (1983–1989) compares life-quality scores according to Karnofsky in patients with intra-cranial who had been operated upon. Karnofsky's performance status was evaluated during a follow-up period of 36 months. The patients were between 20 to 77 years of age; 132 patients had an astrocytoma grade III or IV; 42 patients with brain metastases were investigated; 72 had an astrocytoma grade I + II, and 144 had a meningioma. The median survival in patients with astrocytomas grade III or IV was 12 months; a short period with nearly normal activity (Karnofsky score 75) was followed by rapid deterioration. In patients with brain metastases, postoperatively the median functional ability reached its highest value three weeks after treatment and then decreased continuously (average score from 50–25). In patients with astrocytomas grade I and II, life-quality was reasonably good (mean score up to 75). The score was observed to increase slightly during the first year after treatment. A performance status improvement up to 80 could be obtained in patients with meningiomas; however, 35% were left unfit for work.

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy.

Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and −0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p < 0.001). Results remained significant after excluding patients undergoing (neo)adjuvant treatment. Resection extent showed correlation with postoperative reduction of TGV (R = 0.97, p < 0.001). ROC analysis identified a residual cut-off tumor volume > 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.