A B S T R A C T PurposeThis phase II trial was designed to define the role of O 6 -benzylguanine (O 6 -BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O 6 -BG in combination with temozolomide. Patients and MethodsPatients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O 6 -BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O 6 -BG infusion at a dose of 120 mg/m 2 followed immediately by a 48-hour infusion at a dose of 30 mg/m 2 /d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O 6 -BG infusion at a dose of 472 mg/m 2 . The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. ResultsSixty-six of 67 patients who enrolled were treated with temozolomide and O 6 -BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. ConclusionO 6 -BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

The vesicular monoamine transporter 2 (VMAT2) is localized primarily within the CNS and is responsible for transporting monoamines from the cytoplasm into secretory vesicles. Because reserpine (a VMAT inhibitor) can precipitate depressive-like symptoms in humans, we investigated whether Vmat2 heterozygous (HET) mice present with depressive-like behaviors. The mutants showed locomotor and rearing retardation in the open field and appeared anhedonic to 1 and 1.5% sucrose solutions. Immobility times for Vmat2 heterozygotes were prolonged in forced swim and imipramine normalized this behavior. HET animals also showed enhanced immobility in tail suspension and this response was alleviated by fluoxetine, reboxetine, and bupropion. Stimulated GTP␥S binding indicated that ␣ 2 -adrenergic receptors in HET hippocampus were more sensitive to UK 14,304 (5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine) stimulation than in wild type (WT) mice. In learned helplessness, mice were exposed to a shuttle box for 4 d or were given inescapable foot-shocks for the same time period. On day 5, all animals were tested in shock escape. Failure rates and the latency to escape were similar for WT and HET mice that were only pre-exposed to the test apparatus. In foot-shock groups, learned helplessness was more robust in heterozygotes than in WT controls. Basal secretion of serum corticosterone was not distinguished by genotype; however, corticosterone levels in mutants were more responsive to stress. Anxiety-like responses of WT and HET animals in the open field, light-dark exploration, zero maze, and novelty-suppressed feeding tests were indistinguishable. Collectively, these findings suggest that Vmat2 heterozygotes display a depressive-like phenotype that is devoid of anxiety-like behavior.

The current results indicate that NIFTP is a rare tumor if defined by strict criteria, that both the GEC and UPMC methods indicate abnormalities in NIFTP, and further independent study will be needed to better characterize the molecular and clinical characteristics of NIFTP. Cancer Cytopathol 2016;124:893-900. © 2016 American Cancer Society.