Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.

PURPOSE: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse. PATIENTS AND METHODS: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients. RESULTS: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001). CONCLUSION: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.

Reduced brain volume and white matter alterations in Shank3-deficient rats.

Mutations and deletions in the SHANK3 gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS), which is characterized by intellectual disability, autism spectrum disorder, and sensory hyporeactivity. SHANK3 encodes a key structural component of excitatory synapses important for synaptogenesis. Clinical assessments and limited brain imaging studies of patients with PMS have uncovered regional volume reductions and white matter thinning. While these impairments have been replicated ex vivo in pups of a rat model, brain structure has not been assessed in rats in vivo or in adults. We assessed the brain structure of heterozygous and homozygous adult Shank3-deficient male rats in comparison to wild-type littermates with magnetic resonance imaging using both anatomical assessments and diffusion tensor imaging (DTI). Shank3-deficient rats showed a reduction in overall brain size and the absolute volume of the neocortex, piriform cortex, thalamus, forebrain, inferior and superior colliculi, internal capsule, and anterior commissure. The superior colliculus was decreased in relative volume. DTI revealed that axial diffusion and fractional anisotropy were reduced in the external capsule and mean diffusion was increased in the fornix, suggesting that restriction of diffusion perpendicular to the axis of the axonal fibers was impaired in these white matter tracts. Therefore, Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in PMS. Our results indicate that the loss of a glutamatergic synaptic protein, Shank3, has structural consequences at the level of the whole brain. The brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.

Transient changes in white matter microstructure during general anesthesia.

Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.

PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival.

Microvascular pathology and ischemic lesions contribute substantially to neuronal dysfunction and loss that lead to Alzheimer disease (AD). To facilitate recovery, the brain stimulates neovascularization of damaged tissue via sprouting angiogenesis, a process regulated by endothelial cell (EC) sprouting and the EphB4/ephrinB2 system. Here, we show that in cultures of brain ECs, EphB4 stimulates the VE-cadherin/Rok-α angiogenic complexes known to mediate sprouting angiogenesis. Importantly, brain EC cultures expressing PS1 FAD mutants decrease the EphB4-stimulated γ-secretase cleavage of ephrinB2 and reduce production of the angiogenic peptide ephrinB2/CTF2, the VE-cadherin angiogenic complexes and EC sprouting and tube formation. These data suggest that FAD mutants may attenuate ischemia-induced brain angiogenesis. Supporting this hypothesis, ischemia-induced VE-cadherin angiogenic complexes, levels of neoangiogenesis marker Endoglin, vascular density, and cerebral blood flow recovery, are all decreased in brains of mouse models expressing PS1 FAD mutants. Ischemia-induced brain neuronal death and cognitive deficits also increase in these mice. Furthermore, a small peptide comprising the C-terminal sequence of peptide ephrinB2/CTF2 rescues angiogenic functions of brain ECs expressing PS1 FAD mutants. Together, our data show that PS1 FAD mutations impede the EphB4/ephrinB2-mediated angiogenic functions of ECs and impair brain neovascularization, neuronal survival and cognitive recovery following ischemia. Furthermore, our data reveal a novel brain angiogenic mechanism targeted by PS1 FAD mutants and a potential therapeutic target for ischemia-induced neurodegeneration. Importantly, FAD mutant effects occur in absence of neuropathological hallmarks of AD, supporting that such hallmarks may form downstream of mutant effects on neoangiogenesis and neuronal survival.

Impact of baseline serum IL-8 on metastatic hormone-sensitive prostate cancer outcomes in the Phase 3 CHAARTED trial (E3805).

BACKGROUND: The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/- docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings. METHODS: Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed. RESULTS: Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4-3.6, p = .001; binary >9.3: HR 1.7, 95% CI: 1.2-2.4, p = .007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6-3.3, p < .001; binary: HR 1.8, 95% CI: 1.3-2.5, p < .001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels >9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p = .007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99-1.9, p = .057). CONCLUSIONS: In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene. Neuroanatomical alterations have been reported in both male and female individuals with FXS, yet the morphological underpinnings of these alterations have not been elucidated. In the current study, we found structural changes in both male and female rats that model FXS, some of which are similarly impaired in both sexes, including the superior colliculus and periaqueductal gray, and others that show sex-specific changes. The splenium of the corpus callosum, for example, was only impaired in males. We also found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Furthermore, we found that overall, male rats have higher brain-wide diffusion than female rats. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and reveal an impairment at the level of the axon that could cause structural changes in white matter regions.

Brain of the African wild dog. I. Anatomy, architecture, and volumetrics.

The African wild dog is endemic to sub-Saharan Africa and belongs to the family Canidae which includes domestic dogs and their closest relatives (i.e., wolves, coyotes, jackals, dingoes, and foxes). The African wild dog is known for its highly social behavior, co-ordinated pack predation, and striking vocal repertoire, but little is known about its brain and whether it differs in any significant way from that of other canids. We employed gross anatomical observation, magnetic resonance imaging, and classical neuroanatomical staining to provide a broad overview of the structure of the African wild dog brain. Our results reveal a mean brain mass of 154.08 g, with an encephalization quotient of 1.73, indicating that the African wild dog has a relatively large brain size. Analysis of the various structures that comprise their brains and their topological inter-relationships, as well as the areas and volumes of the corpus callosum, ventricular system, hippocampus, amygdala, cerebellum and the gyrification index, all reveal that the African wild dog brain is, in general, similar to that of other mammals, and very similar to that of other carnivorans. While at this level of analysis we do not find any striking specializations within the brain of the African wild dog, apart from a relatively large brain size, the observations made indicate that more detailed analyses of specific neural systems, particularly those involved in sensorimotor processing, sociality or cognition, may reveal features that are either unique to this species or shared among the Canidae to the exclusion of other Carnivora.

Brain gyrification in wild and domestic canids: Has domestication changed the gyrification index in domestic dogs?

Over the last 15 years, research on canid cognition has revealed that domestic dogs possess a surprising array of complex sociocognitive skills pointing to the possibility that the domestication process might have uniquely altered their brains; however, we know very little about how evolutionary processes (natural or artificial) might have modified underlying neural structure to support species-specific behaviors. Evaluating the degree of cortical folding (i.e., gyrification) within canids may prove useful, as this parameter is linked to functional variation of the cerebral cortex. Using quantitative magnetic resonance imaging to investigate the impact of domestication on the canine cortical surface, we compared the gyrification index (GI) in 19 carnivore species, including six wild canid and 13 domestic dog individuals. We also explored correlations between global and local GI with brain mass, cortical thickness, white and gray matter volume and surface area. Our results indicated that GI values for domestic dogs are largely consistent with what would be expected for a canid of their given brain mass, although more variable than that observed in wild canids. We also found that GI in canids is positively correlated with cortical surface area, cortical thickness and total cortical gray matter volumes. While we found no evidence of global differences in GI between domestic and wild canids, certain regional differences in gyrification were observed.

Respirator usage protects brain white matter from welding fume exposure: A pilot magnetic resonance imaging study of welders.

Welding fume exposure has been associated with structural brain changes and a wide variety of clinical and sub-clinical outcomes including cognitive, behavioral and motor abnormalities. Respirator use has been shown to decrease exposure to welding fumes; however, the associations between respirator use and health outcomes, particularly neurologic health, have been understudied. In this preliminary study, we used diffusion tensor imaging (DTI) to investigate the effectiveness of respirator use in protecting workers' white matter (WM) from the harmful effects related to welding fume exposure. Fractional anisotropy (FA), a common DTI measurement of water diffusion properties, was used as a marker of WM microstructure integrity. We hypothesized that FA in brain regions involved in motor and neurocognitive functions would differ between welders reporting respirator use compared to those not using a respirator. We enrolled a pilot cohort of 19 welders from labor unions in the New York City area. All welders completed questionnaires to assess welding history and occupational health. All completed a DTI acquisition on a 3 T Siemens scanner. Partial least squares discriminant analysis (PLS-DA), a bioinformatic analytical strategy, was used to model the divergence of WM microstructures in 48 regions defined by the ICBM-DTI-81 atlas between respirator users compared to non-users. This yielded an effective discrimination of respirator users from non-users, with the uncinate fasciculus, the cerebellar peduncle and the superior longitudinal fasciculus contributing most to the discrimination of these groups. These white matter tracts are involved in widespread motor and cognitive functions. To our knowledge, this study is the first to suggest a protective effect of respirator on WM microstructure, indicating that the lack of respirator may present unsafe working conditions for welders. These preliminary findings may inform a larger, longitudinal intervention study that would be more appropriate to investigate the potential protective effect of respirator usage on brain white matter in welders.

Scaling of the corpus callosum in wild and domestic canids: Insights into the domesticated brain.

All domesticated mammals exhibit marked reductions in overall brain size, however, it is unknown whether the corpus callosum (CC), an integral white matter fiber pathway for interhemispheric cortical communication, is affected by domestication differentially or strictly in coordination with changes in brain size. To answer this question, we used quantitative magnetic resonance imaging to compare the midsagittal cross-sectional areas of the CC in 35 carnivore species, including eight wild canids and 13 domestic dogs. We segmented rostro-caudal regions of interest for the CC and evaluated correlations with brain mass. The results of this study indicate that under the influence of domestication in canids, the CC scales to brain size in an allometric relationship that is similar to that of wild canids and other carnivores, with relatively high correlation coefficients observed for all regions, except the rostrum. These results indicate that architectural and energetic considerations are likely to tightly constrain variation in caudal components of the CC relative to overall brain size, however fibers passing through the rostrum, putatively connecting prefrontal cortex, are less constrained and therefore may contribute more toward species-specific differences in connectivity. Given the species diversity of the Canidae and the resurgence of interest in the brain of the domestic dog, further studies aimed at characterizing the neural architecture in domesticated species is likely to provide new insights into the effects of domestication, or artificial selection, on the brain.

Social stress induces neurovascular pathology promoting depression.

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Mapping of Brain Activity by Automated Volume Analysis of Immediate Early Genes.

Understanding how neural information is processed in physiological and pathological states would benefit from precise detection, localization, and quantification of the activity of all neurons across the entire brain, which has not, to date, been achieved in the mammalian brain. We introduce a pipeline for high-speed acquisition of brain activity at cellular resolution through profiling immediate early gene expression using immunostaining and light-sheet fluorescence imaging, followed by automated mapping and analysis of activity by an open-source software program we term ClearMap. We validate the pipeline first by analysis of brain regions activated in response to haloperidol. Next, we report new cortical regions downstream of whisker-evoked sensory processing during active exploration. Last, we combine activity mapping with axon tracing to uncover new brain regions differentially activated during parenting behavior. This pipeline is widely applicable to different experimental paradigms, including animal species for which transgenic activity reporters are not readily available.