BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas.

BACKGROUND: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy. METHODS: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data. RESULTS: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events. CONCLUSIONS: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).

Alliance A071401: Phase II Trial of Focal Adhesion Kinase Inhibition in Meningiomas With Somatic NF2 Mutations.

PURPOSE: Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS: Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS: Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION: GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Positron emission tomography imaging of amphetamine-induced dopamine release in the human cortex: a comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride.

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [(11)C]raclopride and [(123)I]IBZM, do not provide sufficient signal to noise ratio to quantify D(2) receptors in extrastriatal areas, such as cortex, where the concentration of D(2) receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D(2) radioligands [(11)C]FLB 457 and [(11)C]fallypride to measure amphetamine-induced changes in DA transmission in the human cortex. D(2) receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg(-1), oral), using both [(11)C]FLB 457 and [(11)C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP(ND)) in eight cortical regions. Under controlled conditions, [(11)C]FLB 457 BP(ND) was 30-70% higher compared with [(11)C]fallypride BP(ND) in cortical regions. Amphetamine induced DA release led to a significant decrease in [(11)C]FLB 457 BP(ND) in five out the eight cortical regions evaluated. In contrast, no significant decrease in [(11)C]fallypride BP(ND) was detected in cortex following amphetamine. The difference between [(11)C]FLB 457 and [(11)C]fallypride ability to detect changes in the cortical D(2) receptor availability following amphetamine is related to the higher signal to noise ratio provided by [(11)C]FLB 457. These findings suggest that [(11)C]FLB 457 is superior to [(11)C]fallypride for measurement of changes in cortical synaptic dopamine.

Positron emission tomography imaging of D(2/3) agonist binding in healthy human subjects with the radiotracer [(11)C]-N-propyl-norapomorphine: preliminary evaluation and reproducibility studies.

OBJECTIVE: (-)-N-[(11)C]-propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist radiotracer suitable for imaging D(2/3) receptors configured in a state of high affinity for agonists using positron emission tomography. The aim of the present study was to define the optimal analytic method to derive accurate and reliable D(2/3) receptor parameters with [(11)C]NPA. METHODS: Six healthy subjects (four females/two males) underwent two [(11)C]NPA scans in the same day. D(2/3) receptor-binding parameters were estimated using kinetic analysis (using one- and two-tissue compartment models) as well as simplified reference tissue method in the three functional subdivisions of the striatum (associative striatum, limbic striatum, and sensorimotor striatum). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (V(T)), binding potential relative to plasma concentration (BP(P)), and binding potential relative to nondisplaceable uptake (BP(ND)). RESULTS: A two-tissue compartment kinetic model adequately described the functional subdivisions of the striatum as well as cerebellum time-activity data. The reproducibility of V(T) was excellent (0.75) in the three functional subdivisions of the striatum. Although SRTM led to an underestimation of BP(ND) values relative to that estimated by kinetic analysis by 8-13%, the values derived using both the methods were reasonably well correlated (r(2) = 0.89, n = 84). Both methods were similarly effective in detecting the differences in [(11)C]NPA BP(ND) between subjects. CONCLUSION: The results of this study indicate that [(11)C]NPA can be used to measure D(2/3) receptors configured in a state of high affinity for the agonists with high reliability and reproducibility in the functional subdivisions of the human striatum.

Quantitative analysis of PiB-PET with FreeSurfer ROIs.

In vivo quantification of ß-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.

Tiagabine increases [11C]flumazenil binding in cortical brain regions in healthy control subjects.

Accumulating evidence indicates that synchronization of cortical neuronal activity at gamma-band frequencies is important for various types of perceptual and cognitive processes and that GABA-A receptor-mediated transmission is required for the induction of these network oscillations. In turn, the abnormalities in GABA transmission postulated to play a role in psychiatric conditions such as schizophrenia might contribute to the cognitive deficits seen in this illness. We measured the ability to increase GABA in eight healthy subjects by comparing the binding of [(11)C]flumazenil, a positron emission tomography (PET) radiotracer specific for the benzodiazepine (BDZ) site, at baseline and in the presence of an acute elevation in GABA levels through the blockade of the GABA membrane transporter (GAT1). Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands (termed 'GABA shift'). Theoretically, such an increase in the affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. GAT1 blockade resulted in significant increases in mean (+/- SD) [(11)C]flumazenil-binding potential (BP(ND)) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.2+/-20.2% (p=0.05), sensory cortex +13.5+/-15.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.4+/-20.2% (p=0.03). The increase in [(11)C]flumazenil-BP(ND) was not accounted for by differences in the plasma-free fraction (f(P); paired t-test p=0.24) or changes in the nonspecific binding (pons V(T), p=0.73). Moreover, the ability to increase GABA strongly predicted (r=0.85, p=0.015) the ability to entrain cortical networks, measured through EEG gamma synchrony during a cognitive control task in these same subjects. Although additional studies are necessary to further validate this technique, these data provide preliminary evidence of the ability to measure in vivo, with PET, acute fluctuations in extracellular GABA levels and provide the first in vivo documentation of a relationship between GABA neurotransmission and EEG gamma-band power in humans.