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Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood–brain barrier disruption (BBBD). Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan–Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively). Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7–78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7–48.3 cm3). Median PFS was 11.5 months (95% CI 7.7–25.9) with 6, 12, 24 and 60 month PFS estimated to be 91.3% (95% CI 69.5–97.8), 47.4% (26.3–65.9), 32.5% (14.4–52.2) and 5.4% (0.4–21.8), respectively. Median OS was 23.1 months (95% CI 12.2–36.9) with 12, 24, and 36 month OS as 77.3% (95% CI 53.6–89.9), 45.0% (22.3–65.3) and 32.1% (12.5–53.8), respectively. Repeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood-brain barrier disruption (BBBD).Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan-Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively).Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7-78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7-48.3 cmRepeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma.

The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial. The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5 mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM. Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5 mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5 mm threshold for target brain lesions when using high resolution MRI with ≤2 mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

Differentiating neoplastic from non-neoplastic intracranial lesions is of paramount importance for patient management. Benign lesions can have many of the features of malignant brain tumors on both computed tomography (CT) and conventional magnetic resonance imaging (MRI). Herewith, we set out to investigate the role of (99m)Tc-Tetrofosmin (⁹⁹(m)Tc-TF) brain SPECT in the differentiation of neoplastic from non-neoplastic intracranial lesions. We prospectively studied, between September 2004 and September 2009, patients with intracranial lesions suspected of being tumors on CT/MRI that were operated on. All patients with suspected tumor on CT/MRI underwent ⁹⁹(m)Tc-TF brain SPECT within a week before surgery and CT/MRI studies. Radiotracer accumulation in intracranial lesions was assessed visually and then a semiquantitative method of image analysis was applied, by calculating the lesion-to-normal (L/N) uptake ratio. We compared the L/N ratios between low-grade gliomas and high-grade gliomas, low and high-grade gliomas and intra-axial non-neoplastic lesions, low and high-grade gliomas and metastases, and typical versus anaplastic meningiomas Ninety patients suffered from neoplastic lesions and 16 harboured non-neoplastic pathologies. There was a significant difference between low-grade gliomas and high-grade gliomas (P = 0.0019). ROC analysis provided 2.8 as the optimum cutoff value thresholding discrimination between these two groups, with 91.3% sensitivity and 83.3% specificity. When comparing gliomas (low and high-grade) with intra axial non-neoplastic lesions the difference was statistically significant (P0.0001). There was no statistically significant difference between gliomas (low and high-grade) and metastases. Regarding meningiomas, there was a statistically significant difference between typical and anaplastic meningiomas (P = 0.0002). ROC analysis provided 9.6 as the optimum cutoff value thresholding discrimination between these two groups, with 96% sensitivity and 100% specificity. (99m)Tc-TF brain SPECT may differentiate neoplastic from non-neoplastic intracranial pathologies and could prove useful for pre-surgical evaluation of intracranial lesions.

Treatment for brain gliomas is a combined approach of surgery, radiation therapy and chemotherapy. Nevertheless, high-grade gliomas usually recur despite treatment. Ionizing radiation therapy to the central nervous system may cause post-radiation damage. Differentiation between post-irradiation necrosis and recurrent glioma on the basis of clinical signs and symptomatology has not been possible. Computed tomography (CT) and magnetic resonance imaging (MRI) suffer from significant limitations when applied to differentiate recurrent brain tumor from radiation necrosis. We reviewed the contribution of recent MRI techniques, single-photon emission CT and positron emission tomography to discriminate necrosis for glioma recurrence. We concluded that despite the progress being made, further research is needed to establish reliable imaging modalities that distinguish between true tumour progression and treatment-related necrosis.

To the Editor:We read with great interest the recent article by Jain et al.[1] on the differentiation of treatment-induced radiationnecrosis from recurrent or progressive brain tumor usingseveral functional imaging modalities. The authorsreviewed the current literature regarding diffusion- andperfusion-weighted magnetic resonance imaging (MRI),MR spectroscopy and positron emission tomography(PET). They discussed the contribution of the aboveimaging modalities in differentiating between recurrentbrain tumor and radiation necrosis as well as theirlimitations.Apart from PET, single photon emission computedtomography (SPECT) is a molecular imaging modality thatis more widely available and at lower cost. We haveacquired significant experience with the brain tumorimaging properties of technetium-99 m-tetrofosmin(

Meningiomas account for about 30% of all intracranial tumors. Evaluation of their proliferation rate is useful for assessing their biological behavior. We evaluated prospectively whether (99m)Tc-Tetrofosmin ((99m)Tc-TF) uptake in meningiomas correlates with cellular proliferative activity and with tumor grade. We prospectively studied 18 meningioma cases. Brain single-photon emission computed tomography (SPECT) by (99m)Tc-TF was performed within a week prior to surgical excision. In the excised tumor specimens we assessed Ki-67 antigen expression. 14 of 18 patients had benign meningiomas, while the remaining four had anaplastic meningiomas. A significant correlation was found between both (99m)Tc-TF uptake and tumor grade (r = 0.722, P = 0.001) and between (99m)Tc-TF uptake and Ki-67 expression (r = 0.930, P0.001). There was a significant correlation between the intensity of tracer uptake and tumor recurrence at 1 year postoperative (r = 0.574, P = 0.02). This pilot study implies that (99m)Tc-TF brain SPECT could prove useful in differentiating benign from anaplastic meningiomas and is a potential indicator of their proliferative activity.

The biological behavior and prognosis of gliomas depend largely on cellular proliferation, resistance to chemotherapy, and metastatic potential. Proliferative propensity has significant implications on patient management but its assessment requires tissue sampling; the non-invasive estimation of brain tumor proliferation represents therefore a major goal. Pentavalent technetium-99 m dimercapto-succinic acid [99m Tc-(V)DMSA] is a tumor-seeking radiotracer displaying affinity for gliomas; its intracellular accumulation is directly linked to cell proliferation. We performed a tomographic 99m Tc-(V)DMSA brain scan in a 35-year-old male baring a recurrent glioblastoma multiforme, to depict its proliferative disposition. The patient had been diagnosed 14 months earlier and had been submitted to surgery, followed by adjuvant radiotherapy and temozolomide-based chemotherapy. On clinical suspicion of recurrence 5 months later, magnetic resonance imaging (MRI) revealed a lesion at the site of preceded surgery, which was treated by imatinib mesylate. No improvement was ascertained the following months and radiographic assessment verified tumor progression. Scintitomography revealed avid radiotracer uptake in the entirety of the lesion (the distribution of radioactivity closely conforming to the morphological tumor boundaries), an indication that the neoplasm demonstrated no substantial proliferation decline in response to imatinib. The patient deceased a few weeks later. Mounting in vivo and in vitro evidence indicates that 99m Tc-(V)DMSA is a credible non-invasive proliferation depicter, its cellular accumulation linked closely to phosphate uptake and kinase pathway activation. A potential role in patient management, prognosis estimation, and therapy response monitoring could occur for this tracer.

F-FDG) in the follow-up of patients sufferingfromglioblastomamultiforme[1].Theauthorsstudied28caseswith both FDG- and MET-PET, after their initial treatment;they found no correlation between tumoral uptake of eithertracer and survival. Furthermore, both PET tracers providedinconclusive results with reference to the discrimination be-tween tumor recurrence and radiation injury [ 1].ApartfromPET,conventionalfunctionalbrainimagingbysingle-photon emission computed tomography (SPECT) hasalso been evaluated in gliomas. Thallium-201 (