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Glioblastoma is the most common malignant brain tumor in adults. Standard treatment includes tumor resection, radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ). TMZ methylates DNA, whereas O6-methylguanine DNA methyltransferase (MGMT) counteracts TMZ effects by removing the intended proteasomal degradation signal. Non-functional MGMT mediates the mismatch repair (MMR) system, leading to apoptosis after futile repair attempts. This study investigated the associations between MGMT promoter methylation, MGMT and MMR protein expression, and their effect on overall survival (OS) and progression-free survival (PFS) in patients with glioblastoma. MGMT promoter methylation was assessed in 42 treatment-naïve patients with glioblastoma WHO grade IV by pyrosequencing. MGMT and MMR protein expression was analyzed using immunohistochemistry. MGMT promoter methylation was present in 52%, whereas patients <70 years of age revealed a significantly longer OS using a log-rank test and a significance threshold of p ≤ 0.05. MGMT protein expression and methylation status showed no correlation. MMR protein expression was present in all patients independent of MGMT status and did not influence OS and PFS. Overall, MGMT promoter methylation implicates an improved OS in patients with glioblastoma aged <70 years. In the elderly, the extent of surgery has an impact on OS rather than the MGMT promoter methylation or protein expression. [ABSTRACT FROM AUTHOR]

Background: Gastrin-releasing peptide receptors (GRPRs) are molecular imaging targets in multiple malignancies. Recently, NeoBOMB1, a 68Ga-labelled antagonist to GRPRs, was developed for PET. Here we report the outcome of a Phase I/IIa clinical trial (EudraCT 2016-002053-38) describing diagnostic properties and covariates influencing uptake of 68Ga-NeoBOMB1 in oligometastatic gastrointestinal stromal tumor (GIST) patients. Methods: Nine patients with advanced GIST using PET/CT (computed tomography) were included. After kit-based 68Ga-NeoBOMB1 preparation with a licensed 68Ge/68Ga generator, 3 MBq/kg body weight were injected intravenously. PET/CT included dynamic and static PET scans 5, 12 and 18 min and 1, 2, and 3−4 h post injection (first six patients) and static PET scans 2 and 3−4 h post injection (last three participants). Tumor targeting was assessed on a per-lesion and per-patient basis. Results: Six patients showed visible radiotracer uptake in at least one tumor lesion. Seventeen out of 37 tumor lesions exhibited significant 68Ga-NeoBOMB1 uptake (median SUVmax 11.8 [range 2.8−51.1] 2 h p.i. and 13.2 [range 2.5−53.8] 3−4 h p.i) and improved lesion-to-background contrast over time. Five lesions (13.5%) were identified only by 68Ga-NeoBOMB1-PET, with no correlation on contrast-enhanced CT. Three patients showed no radiotracer accumulation in any lesions. Tracer uptake correlated with male sex (p < 0.0001), higher body mass index (p = 0.007), and non-necrotic lesion appearance (p = 0.018). There was no association with whole-lesion contrast enhancement, hepatic localization, mutational status, or disease duration. Conclusions: 68Ga-NeoBOMB1-PET exhibits variable tumor uptake in advanced-stage GIST patients, correlating with lesion vitality based on CT contrast uptake, opening the possibility of a theragnostic approach in selected cases.