SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS).

PURPOSE: Dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) are two common subtypes of soft-tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting cyclin-dependent kinase 4 and 6 (CDK4/6) in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients. PATIENTS AND METHODS: This was a single arm, open label, multicenter phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression-free rate (PFR) at 16 weeks. Secondary endpoints included progression-free survival (PFS) and overall survival, safety and biomarker analyses. RESULTS: In the DDL cohort, 33.3% [95% confidence interval (CI), 15.6%-55.3%] of patients were progression-free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI, 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI, 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%), and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor. CONCLUSIONS: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects.

Age at First Exposure to Tackle Football is Associated with Cortical Thickness in Former Professional American Football Players.

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely.

Increased Functional Activation of Limbic Brain Regions during Negative Emotional Processing in Migraine.

Pain is both an unpleasant sensory and emotional experience. This is highly relevant in migraine where cortical hyperexcitability in response to sensory stimuli (including pain, light, and sound) has been extensively reported. However, migraine may feature a more general enhanced response to aversive stimuli rather than being sensory-specific. To this end we used functional magnetic resonance imaging to assess neural activation in migraineurs interictaly in response to emotional visual stimuli from the International Affective Picture System. Migraineurs, compared to healthy controls, demonstrated increased neural activity in response to negative emotional stimuli. Most notably in regions overlapping in their involvement in both nociceptive and emotional processing including the posterior cingulate, caudate, amygdala, and thalamus (cluster corrected, p < 0.01). In contrast, migraineurs and healthy controls displayed no and minimal differences in response to positive and neutral emotional stimuli, respectively. These findings support the notion that migraine may feature more generalized altered cerebral processing of aversive/negative stimuli, rather than exclusively to sensory stimuli. A generalized hypersensitivity to aversive stimuli may be an inherent feature of migraine, or a consequential alteration developed over the duration of the disease. This proposed cortical-limbic hypersensitivity may form an important part of the migraine pathophysiology, including psychological comorbidity, and may represent an innate sensitivity to aversive stimuli that underpins attack triggers, attack persistence and (potentially) gradual headache chronification.

Increased Amplitude of Thalamocortical Low-Frequency Oscillations in Patients with Migraine.

UNLABELLED: For many years, neurobiological theories have emphasized the importance of neuronal oscillations in the emergence of brain function. At the same time, clinical studies have shown that disturbances or irregularities in brain rhythms may relate to various common neurological conditions, including migraine. Increasing evidence suggests that the CNS plays a fundamental role in the predisposition to develop different forms of headache. Here, we present human imaging data that strongly support the presence of abnormal low-frequency oscillations (LFOs) in thalamocortical networks of patients in the interictal phase of migraine. Our results show that the main source of arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus. In addition, spontaneous LFOs in the thalamus were selectively associated with the headache attack frequency, meaning that the varying amplitude of dysrhythmia could predispose patients to recurrent attacks. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability. We further speculate that the intrinsic dynamics of thalamocortical network oscillations are crucial for early sensory processing and therefore could underlie important pathophysiological processes involved in multisensory integration. SIGNIFICANCE STATEMENT: In many cases, migraine attacks are thought to begin centrally. A major obstacle to studying intrinsic brain activity has been the identification of the precise anatomical structures and functional networks that are involved in migraine. Here, we present imaging data that strongly support the presence of abnormal low-frequency oscillations in thalamocortical networks of patients in the interictal phase of migraine. This arrhythmic activity was localized to the higher-order thalamic relays of the medial dorsal nucleus and was selectively associated with headache attack frequency. Rhythmic cortical feedback to the thalamus is a major factor in the amplification of thalamocortical oscillations, making it a strong candidate for influencing neuronal excitability and higher-level processes involved in multisensory integration.

Cortico-Cortical Connections of Primary Sensory Areas and Associated Symptoms in Migraine.

Migraine is a recurring, episodic neurological disorder characterized by headache, nausea, vomiting, and sensory disturbances. These events are thought to arise from the activation and sensitization of neurons along the trigemino-vascular pathway. From animal studies, it is known that thalamocortical projections play an important role in the transmission of nociceptive signals from the meninges to the cortex. However, little is currently known about the potential involvement of cortico-cortical feedback projections from higher-order multisensory areas and/or feedforward projections from principle primary sensory areas or subcortical structures. In a large cohort of human migraine patients (N = 40) and matched healthy control subjects (N = 40), we used resting-state intrinsic functional connectivity to examine the cortical networks associated with the three main sensory perceptual modalities of vision, audition, and somatosensation. Specifically, we sought to explore the complexity of the sensory networks as they converge and become functionally coupled in multimodal systems. We also compared self-reported retrospective migraine symptoms in the same patients, examining the prevalence of sensory symptoms across the different phases of the migraine cycle. Our results show widespread and persistent disturbances in the perceptions of multiple sensory modalities. Consistent with this observation, we discovered that primary sensory areas maintain local functional connectivity but express impaired long-range connections to higher-order association areas (including regions of the default mode and salience network). We speculate that cortico-cortical interactions are necessary for the integration of information within and across the sensory modalities and, thus, could play an important role in the initiation of migraine and/or the development of its associated symptoms.

The Insula: A "Hub of Activity" in Migraine.

The insula, a "cortical hub" buried within the lateral sulcus, is involved in a number of processes including goal-directed cognition, conscious awareness, autonomic regulation, interoception, and somatosensation. While some of these processes are well known in the clinical presentation of migraine (i.e., autonomic and somatosensory alterations), other more complex behaviors in migraine, such as conscious awareness and error detection, are less well described. Since the insula processes and relays afferent inputs from brain areas involved in these functions to areas involved in higher cortical function such as frontal, temporal, and parietal regions, it may be implicated as a brain region that translates the signals of altered internal milieu in migraine, along with other chronic pain conditions, through the insula into complex behaviors. Here we review how the insula function and structure is altered in migraine. As a brain region of a number of brain functions, it may serve as a model to study new potential clinical perspectives for migraine treatment.

Primary Somatosensory Cortices Contain Altered Patterns of Regional Cerebral Blood Flow in the Interictal Phase of Migraine.

The regulation of cerebral blood flow (CBF) is a complex integrated process that is critical for supporting healthy brain function. Studies have demonstrated a high incidence of alterations in CBF in patients suffering from migraine with and without aura during different phases of attacks. However, the CBF data collected interictally has failed to show any distinguishing features or clues as to the underlying pathophysiology of the disease. In this study we used the magnetic resonance imaging (MRI) technique-arterial spin labeling (ASL)-to non-invasively and quantitatively measure regional CBF (rCBF) in a case-controlled study of interictal migraine. We examined both the regional and global CBF differences between the groups, and found a significant increase in rCBF in the primary somatosensory cortex (S1) of migraine patients. The CBF values in S1 were positively correlated with the headache attack frequency, but were unrelated to the duration of illness or age of the patients. Additionally, 82% of patients reported skin hypersensitivity (cutaneous allodynia) during migraine, suggesting atypical processing of somatosensory stimuli. Our results demonstrate the presence of a disease-specific functional deficit in a known region of the trigemino-cortical pathway, which may be driven by adaptive or maladaptive functional plasticity. These findings may in part explain the altered sensory experiences reported between migraine attacks.

Female migraineurs show lack of insular thinning with age.

Gray matter loss in cortical regions is a normal ageing process for the healthy brain. There have been few studies on the process of ageing of the brain in chronic neurological disorders. In this study, we evaluated changes in the cortical thickness by age in 92 female subjects (46 patients with migraine and 46 healthy controls) using high-field magnetic resonance imaging. The results indicate that in contrast to healthy subjects, migraineurs show a lack of thinning in the insula by age. The functional significance of the lack of thinning is unknown, but it may contribute to the overall cortical hyperexcitability of the migraine brain because the region is tightly involved in a number of major brain networks involved in interoception, salience, nociception, and autonomic function, including the default mode network.