Olfactory function as an independent prognostic factor in glioblastoma.

OBJECTIVE: To determine the role of olfactory function in patients with glioblastoma multiforme (GBM) as a prognostic clinical measure. METHODS: In a prospective case-control study, olfactory testing was performed in 73 patients with primary GBM at baseline during first-line treatment and at later follow-ups. An age-matched control cohort consisted of 49 patients with neurologic diseases, excluding those known to affect olfactory function per se. Depending on the olfactory testing score, patients were allotted to a hyposmia group (HG) or normosmia group (NG). MRI analysis was performed to assess whether tumor location affects olfactory pathways. RESULTS: Patients with GBM had olfactory dysfunction significantly more often compared to the control cohort (p = 0.003). Tumor location could not explain this finding since no relevant difference in MRI-based olfactory pathway involvement was found between HG and NG (p = 0.131). Patients with olfactory dysfunction had significantly worse overall survival (OS) and progression-free survival (PFS) compared to those without dysfunction (median OS 20.9 vs 40.6 months, p = 0.035; median PFS, 9 vs 19 months, p = 0.022). Multivariate analysis in patients without MRI-based involvement of olfactory pathways confirmed olfaction is an independent prognostic factor for OS (hazard ratio [HR] 0.43; p = 0.042) and PFS (HR 0.51; p = 0.049). CONCLUSION: This pilot study provides the first indication that olfactory dysfunction is frequently observed in GBM and may be associated with worse survival outcome in GBM. However, validation of these results in an independent cohort is needed.

Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial.

BACKGROUND: We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. METHODS: In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. RESULTS: At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42). CONCLUSIONS: The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

Quality of life in the GLARIUS trial randomizing bevacizumab/irinotecan versus temozolomide in newly diagnosed, MGMT-nonmethylated glioblastoma.

Background: The GLARIUS trial, which investigated the efficacy of bevacizumab (BEV)/irinotecan (IRI) compared with standard temozolomide in the first-line therapy of O6-methylguanine-DNA methyltransferase (MGMT)-nonmethylated glioblastoma, showed that progression-free survival was significantly prolonged by BEV/IRI, while overall survival was similar in both arms. The present report focuses on quality of life (QoL) and Karnofsky performance score (KPS) during the whole course of the disease. Methods: Patients (n = 170) received standard radiotherapy and were randomized (2:1) for BEV/IRI or standard temozolomide. At least every 3 months KPS was determined and QoL was measured using the European Organisation for Research and Treatment of Cancer 30-item Core Quality of Life and 20-item Brain Neoplasm questionnaires. A generalized estimating equation (GEE) model evaluated differences in the course of QoL and KPS over time. Also, the time to first deterioration and the time to postprogression deterioration were analyzed separately. Results: In all dimensions of QoL and KPS, GEE analyses and time to first deterioration analyses did not detect significant differences between the treatment arms. At progression, 82% of patients receiving second-line therapy in the standard arm received BEV second-line therapy. For the dimensions of motor dysfunction and headaches, time to postprogression deterioration was prolonged in the standard arm receiving crossover second-line BEV in the vast majority of patients at the time of evaluation. Conclusions: GLARIUS did not find indications for a BEV-induced detrimental effect on QoL in first-line therapy of MGMT-nonmethylated GBM patients. Moreover, GLARIUS provided some indirect corroborative data supporting the notion that BEV may have beneficial effects upon QoL in relapsed GBM.

The earlier the better? Bevacizumab in the treatment of recurrent MGMT-non-methylated glioblastoma.

PURPOSE: The adequate second-line therapy of patients with glioblastoma (GBM) is a matter of ongoing debate. This particularly applies to patients with a non-methylated MGMT promotor who are known to have a poor response to alkylating chemotherapy. In some countries, antiangiogenic therapy with BEV is applied as second-line therapy, and in others nitrosourea therapy is second-line choice. It is an open question whether the delay of BEV to third-line therapy has a negative impact on survival. METHODS: A total of 61 adult patients (median age 56.9 years) with MGMT-non-methylated relapsed GBM treated with BEV (n = 45) or nitrosourea (n = 16) as second-line therapy were analyzed retrospectively and compared regarding progression-free survival (PFS) and overall survival (OS). RESULTS: Patients treated with second-line BEV had longer median PFS (107 days, 95 % CI 80.7-133.2 days) than patients with second-line nitrosourea (52 days, 95 % CI 36.3-67.7 days, P = 0.011, logrank test). However, there was no significant difference in overall survival (BEV median 170 days, 95 % CI 87.2-252.8 days; nitrosourea median 256 days, 95 % CI 159.9-352.0 days, P = 0.468). PFS was similar after BEV third-line therapy (median 117 days, 95 % CI 23.6-210.4 days) as compared to second-line BEV therapy (median 107 days, 95 % CI 80.7-133.3 days, P = 0.584). CONCLUSION: Our findings suggest that early treatment with BEV in patients with MGMT-non-methylated relapsed GBM is associated with a better PFS, but not with superior OS, possibly implicating that the early, i.e., second-line, use of BEV is not mandatory and BEV treatment may safely be delayed to third-line therapy in this subgroup of patients.

Phase I trial of dovitinib (TKI258) in recurrent glioblastoma.

PURPOSE: Dovitinib (TKI258) is an oral multi-tyrosine kinase inhibitor of FGFR, VEGFR, PDGFR ß, and c-Kit. Since dovitinib is able to cross the blood-brain barrier and targets brain tumor-relevant pathways, we conducted a phase I trial to demonstrate its safety in recurrent glioblastoma (GBM). PATIENTS AND METHODS: Patients with first or second GBM recurrence started treatment with the maximal tolerated dose (MTD) previously established in systemic cancer patients (500 mg/d, 5 days on/2 days off). A modified 3 + 3 design in three cohorts (500, 400, 300 mg) was used. RESULTS: Twelve patients were enrolled. Seventy-two adverse events (AEs) occurred and 16.7 % of AEs were classified as ≥CTC grade 3 toxicity, mainly including hepatotoxicity and hematotoxicity. Only one out of six patients of the 300-mg cohort showed grade 3 toxicity. The PFS-6 rate was 16.7 %, and it was not associated with detection of the FGFR-TACC gene fusion in the tumor. CONCLUSION: Dovitinib is safe in patients with recurrent GBM and showed efficacy in only some patients unselected for target expression. The recommended phase II dose of 300 mg would be substantially lower than the recently established MTD in systemic cancer patients. Further personalized trials are recommended.

18F-fluoroethyl-L-tyrosine positron emission tomography for the differential diagnosis of tumefactive multiple sclerosis versus glioma: A case report.

Large demyelinating inflammatory central nervous system (CNS) lesions may present with contrast enhancement on magnetic resonance imaging and may mimic CNS tumors such as glioma. In ambiguous cases, new diagnostic tools that may be helpful for distinguishing between demyelinating inflammatory and neoplastic CNS lesions are required. The current study presents the case of a patient with a large contrast-enhanced frontal brain lesion, who was initially diagnosed with tumefactive multiple sclerosis. Following the progression of the brain lesion, an 18F-fluoroethyl-L-tyrosine positron emission tomography (18F-FET PET) was performed, revealing markedly elevated static 18F-FET uptake parameters along with time activity-curves consistent with glioma. Subsequently, a biopsy was undertaken, which confirmed the presence of anaplastic oligoastrocytoma. This case illustrates that 18F-FET PET may provide useful diagnostic information in cases where distinction between neoplastic and demyelinating inflammatory CNS lesions is challenging. However, further systematic and prospective analyses are warranted to explore the value of this method in this setting.

Late Pseudoprogression in Glioblastoma: Diagnostic Value of Dynamic O-(2-[18F]fluoroethyl)-L-Tyrosine PET.

PURPOSE: Pseudoprogression (PsP) is characterized by therapy-associated but not tumor growth-associated increases of contrast-enhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy, PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET-PET) to approach the diagnostic dilemma. EXPERIMENTAL DESIGN: Twenty-six patients with glioblastoma that presented with increasing contrast-enhancing lesions later than 3 months after completion of radiochemotherapy underwent (18)F-FET-PET. Maximum and mean tumor/brain ratios (TBRmax and TBRmean) of (18)F-FET uptake as well as time-to-peak (TTP) and patterns of the time-activity curves were determined. The final diagnosis of true progression versus late PsP was based on follow-up MRI using RANO criteria. RESULTS: Late PsP occurred in 7 patients with a median time from radiochemotherapy completion of 24 weeks while the remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with late PsP (TBRmax 2.4 ± 0.1 vs. 1.5 ± 0.2, P = 0.003; TBRmean 2.1 ± 0.1 vs. 1.5 ± 0.2, P = 0.012) whereas TTP was significantly shorter (mean TTP 25 ± 2 vs. 40 ± 2 min, P < 0.001). ROC analysis yielded an optimal cutoff value of 1.9 for TBRmax to differentiate between true progression and late PsP (sensitivity 84%, specificity 86%, accuracy 85%, P = 0.015). CONCLUSIONS: O-(2-[(18)F]fluoroethyl)-L-tyrosine PET provides valuable information in assessing the elusive phenomenon of late PsP. Clin Cancer Res; 22(9); 2190-6. ©2015 AACR.

Carmustine (BCNU) plus Teniposide (VM26) in recurrent malignant glioma.

BACKGROUND: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking. METHODS: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m(2), day 1/42) and VM26 (45-60 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity. RESULTS: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed. CONCLUSION: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.

Dietary nitrate supplementation improves revascularization in chronic ischemia.

BACKGROUND: Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known. METHODS AND RESULTS: Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash. CONCLUSIONS: Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.