Mary McGraw

Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma: clinical article.

OBJECTnLaser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose-escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM).nnnMETHODSnAdults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation.nnnRESULTSnTen patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals-Case Medical Center). Their average age was 55 years (range 34-69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70-90). The mean tumor volume was 6.8 ± 5 cm(3) (range 2.6-19 cm(3)), the percentage of tumor treated was 78% ± 12% (range 57%-90%), and the conformality index was 1.21 ± 0.33 (range 1.00-2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62-767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose.nnnCONCLUSIONSnNeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. CLINICAL TRIAL REGISTRATION NO.: NCT00747253 ( ClinicalTrials.gov ).

Family History of Cancer in Benign Brain Tumor Subtypes Versus Gliomas

Purpose: Family history is associated with gliomas, but this association has not been established for benign brain tumors. Using information from newly diagnosed primary brain tumor patients, we describe patterns of family cancer histories in patients with benign brain tumors and compare those to patients with gliomas. Methods: Newly diagnosed primary brain tumor patients were identified as part of the Ohio Brain Tumor Study. Each patient was asked to participate in a telephone interview about personal medical history, family history of cancer, and other exposures. Information was available from 33 acoustic neuroma (65%), 78 meningioma (65%), 49 pituitary adenoma (73.1%), and 152 glioma patients (58.2%). The association between family history of cancer and each subtype was compared with gliomas using unconditional logistic regression models generating odds ratios (ORs) and 95% confidence intervals. Results: There was no significant difference in family history of cancer between patients with glioma and benign subtypes. Conclusion: The results suggest that benign brain tumor may have an association with family history of cancer. More studies are warranted to disentangle the potential genetic and/or environmental causes for these diseases.

Effect of alternative temozolomide schedules on glioblastoma O 6-methylguanine-DNA methyltransferase activity and survival

Background:O6-methylguanine-DNA methyltransferase (MGMT) expression in glioblastoma correlates with temozolomide resistance. Dose-intense temozolomide schedules deplete MGMT activity in peripheral blood mononuclear cells; however, no published data exist evaluating the effect of temozolomide schedules on intracranial tumour MGMT activity.Methods:Human glioblastoma cells (GBM43) with an unmethylated MGMT promoter were implanted intracranially in immunodeficient rodents. Three weeks later, animals received temozolomide 200u2009mgu2009m−2 for 5 days (schedule A, standard dose) or 100u2009mgu2009m−2 for 21 days (schedule B, dose intense).Results:Tumour MGMT activity was depleted by day 6 in both treatment groups compared with baseline. O6-methylguanine-DNA methyltransferase activity returned to baseline by day 22 in the schedule A group, but remained suppressed in the schedule B group. By day 29, MGMT activity had returned to baseline in both groups. Mean tumour volume was significantly decreased compared with untreated controls with either schedule (P<0.01), although neither schedule was superior (P=0.60). Median survival was 64, 42, and 28 days for schedule A, schedule B, and no drug, respectively (P<0.001 A or B vs control, P=NS A vs B).Conclusions:Dose-intense temozolomide prolongs tumour MGMT activity depletion compared with standard dosing, however, survival was not improved in this model.

Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis

Glioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile of LGGs.

Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis

Glioblastoma (GBM) remains uniformly lethal, and despite a large accumulation of immune cells in the microenvironment, there is limited antitumor immune response. To overcome these challenges, a comprehensive understanding of GBM systemic immune response during disease progression is required. Here, we integrated multiparameter flow cytometry and mass cytometry TOF (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing flow cytometry analysis in a cohort of 259 patients ranging from benign to malignant primary and metastatic brain tumors, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in peripheral blood but not immunosuppressive Tregs. In GBM patient tissue, we found that increased MDSC levels in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from newly diagnosed GBM patients revealed that reduced MDSCs over time were accompanied by a concomitant increase in DCs. GBM patients with extended survival also had reduced MDSCs, similar to the levels of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis.

Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (pu2009=u20090.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients.