Benefit of adaptive CT-based treatment planning in high-dose-rate endorectal brachytherapy for rectal cancer

Publication date: Available online 28 September 2017
Source:Brachytherapy
Author(s): Roy P.J. van den Ende, Eva C. Rijkmans, Ellen M. Kerkhof, Remi A. Nout, Martijn Ketelaars, Mirjam S. Laman, Corrie A.M. Marijnen, Uulke A. van der Heide
PurposeIn this planning study, we investigated the dosimetric benefit of repeat CT-based treatment planning at each fraction vs. the use of a single CT-based treatment plan for all fractions for high-dose-rate endorectal brachytherapy (HDREBT) for rectal cancer.Methods and MaterialsWe included 11 patients that received a CT scan with applicator in situ for all three fractions. The treatment plan of the first fraction was projected on the repeat CT scans to simulate the use of a single treatment plan. In addition, replanning was performed on the repeat CT scans, and these were compared to the corresponding projected treatment plans.ResultsRepeat CT-based treatment planning resulted on average in a 21% higher (p = 0.01) conformity index compared to single CT-based treatment planning. Projecting the initial treatment plan to the repeat CT scans of fraction two and three, 12/22 fractions reached a CTV D98 of 85% of the prescribed dose of 7 Gy, which increased to 14/22 using replanning. For the remaining fractions, median CTV D98 was 4.2 Gy, and an intervention would be necessary to correct applicator balloon setup or to remove remaining air and/or feces between the CTV and the applicator.ConclusionsUsing a single CT-based treatment plan for all fractions may result in a suboptimal treatment at later fractions. Therefore, repeat CT imaging should be the minimal standard practice in HDREBT for rectal cancer to determine whether an intervention would be necessary. Replanning based on repeat CT imaging resulted in more conformal treatment plans and is therefore recommended.



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The validity of Acuros BV and TG-43 for high-dose-rate brachytherapy superficial mold treatments

Publication date: Available online 28 September 2017
Source:Brachytherapy
Author(s): Eeva L. Boman, Thomas W.S. Satherley, Nanette Schleich, Dean B. Paterson, Lynne Greig, Rob J.W. Louwe
PurposeThe purpose of this work is to validate the Acuros BV dose calculation algorithm for high-dose-rate (HDR) brachytherapy superficial mold treatments in the absence of full scatter conditions and compare this with TG-43 dose calculations. We also investigate the impact of additional back scatter material (bolus) applied above surface molds to the dose distributions under the mold.Methods and MaterialsThe absorbed dose at various depths was compared for simulations performed using either TG-43 or Acuros BV dose calculations. Parameter variations included treatment area, thickness of the bolus, and surface shape (flat or spherical). Film measurements were carried out in a flat phantom.ResultsAcuros BV calculations and film measurements agreed within 1.5% but were up to 15% lower than TG-43 dose calculations when no bolus was applied above the treatment catheters. The difference in dose at the prescription depth (1 cm below the central catheter) increased with increasing treatment area: 3.3% difference for a 3 × 3.5 cm² source loading area, 7.4% for 8 × 9 cm², and 13.4% for 18 × 19 cm². The dose overestimation of the TG-43 model decreased when bolus was added above the treatment catheters.ConclusionsThe TG-43 dosimetry formalism cannot model surface mold treatments in the absence of full scatter conditions within 5% for loading areas larger than approximately 5 × 5 cm². The TG-43 model results in an overestimation of the delivered dose, which increases with treatment area. This confirms the need for model-based dose calculation algorithms as discussed in TG-186.



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Editorial

The cover of this issue relates to an article by Greg Weir and colleagues who describe a chemogenetic strategy to treat experimental neuropathic pain. Chemogenetics refers to the expression of an exogenous receptor, most commonly using a viral vector, which can subsequently be activated by a chemical ligand to trigger a biological action. Weir et al. targeted a mutated glutamate-gated chloride channel from C. elegans, modified to render it insensitive to glutamate, to dorsal root ganglia neurons of mice that had received a peripheral nerve injury to model neuropathic pain. Upon treatment with the anthelmintic drug ivermectin to activate the channel, treated mice exhibited less pain-related hypersensitivity behaviour, as expected from chloride-channel mediated inhibition of nociceptors. In an accompanying Scientific Commentary Allan Basbaum considers some of the challenges to bring such a strategy to the clinic.

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Connectome-based models of the epileptogenic network: a step towards epileptomics?

This scientific commentary refers to 'Anatomic consistencies across epilepsies: a stereotactic-EEG informed high-resolution structural connectivity study', by Besson et al. (doi:10.1093/brain/awx181).

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Chemogenetic management of neuropathic pain

This scientific commentary refers to 'Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source', by Weir et al. (doi:10.1093/brain/awx201).

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Spreading depolarization and acute ischaemia in subarachnoid haemorrhage: the role of mass depolarization waves

This scientific commentary refers to 'Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction', by Hartings et al. (doi:10.1093/brain/awx214).

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Migraine and risk of stroke: a national population-based twin study

Abstract

Numerous studies have indicated an increased risk for stroke in patients with migraine, especially migraine with aura; however, many studies used self-reported migraine and only a few controlled for familial factors. We aimed to investigate migraine as a risk factor for stroke in a Swedish population-based twin cohort, and whether familial factors contribute to an increased risk. The study population included twins without prior cerebrovascular disease who answered a headache questionnaire during 1998 and 2002 for twins born 1935–58 and during 2005–06 for twins born between 1959 and 1985. Migraine with and without aura and probable migraine was defined by an algorithm mapping on to clinical diagnostic criteria according to the International Classification of Headache Disorders. Stroke diagnoses were obtained from the national patient and cause of death registers. Twins were followed longitudinally, by linkage of national registers, from date of interview until date of first stroke, death, or end of study on 31 Dec 2014. In total, 8635 twins had any migraineous headache, whereof 3553 had migraine with aura and 5082 had non-aura migraineous headache (including migraine without aura and probable migraine), and 44 769 twins had no migraine. During a mean follow-up time of 11.9 years we observed 1297 incident cases of stroke. The Cox proportional hazards model with attained age as underlying time scale was used to estimate hazard ratios with 95% confidence intervals for stroke including ischaemic and haemorrhagic subtypes related to migraine with aura, non-aura migraineous headache, and any migraineous headache. Analyses were adjusted for gender and cardiovascular risk factors. Where appropriate; within-pair analyses were performed to control for confounding by familial factors. The age- and gender-adjusted hazard ratio for stroke related to migraine with aura was 1.27 (95% confidence interval 1.00–1.62), P = 0.05, and 1.07 (95% confidence interval 0.91–1.26), P = 0.39 related to any migraineous headache. Multivariable adjusted analyses showed similar results. When stratified by gender and attained age of ≤50 or >50 years, the estimated hazard ratio for stroke was higher in twins younger than 50 years and in females; however, non-significant. In the within-pair analysis, the hazard ratio for stroke related to migraine with aura was attenuated [hazard ratio 1.09 (95% confidence interval 0.81–1.46), P = 0.59]. In conclusion, we observed no increased stroke risk related to migraine overall but there was a modestly increased risk for stroke related to migraine with aura, and within-pair analyses suggested that familial factors might contribute to this association.

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Mutations in DNM1L , as in OPA1 , result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission

Abstract

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l^+/− mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.

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Reconnecting with Joseph and Augusta Dejerine: 100 years on

Bajada et al. mark the centenary of Joseph Dejerine's death by demonstrating the continuing relevance of his research with his long-standing collaborator, Augusta Dejerine-Klumpke, on the white matter pathways of the brain to modern-day connectional anatomy. A first English translation of the original work is provided in the Supplementary Materials.

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Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation

Sir,

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WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Abstract

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

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Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke

Abstract

Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10⁻⁶). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.

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Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly

Abstract

Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.

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Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction

Abstract

See Ghoshal and Claassen (doi:10.1093/brain/awx226) for a scientific commentary on this article.Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P's < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.

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The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice

Abstract

Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.

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A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction

Abstract

Olfactory dysfunction is common in Parkinson's disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson's disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson's disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson's disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson's disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson's disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson's disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson's disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson's disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson's disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson's disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson's disease.

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Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

Abstract

Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients.

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Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants

Abstract

Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands—delta-theta (2–8 Hz); alpha (8–12 Hz); beta (12–30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.

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A singular person with multiple interests

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On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms?

Sir,

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Reply: On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms?

Sir,

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PRUNE1 : a disease-causing gene for secondary microcephaly

Sir,

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Intrapartum assessment of fetal well-being

1A012A043J02

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Molecular Tumor Boards: Current Practice and Future Needs

Abstract

Background

due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as Whole Exome- and -Genome Sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.

Methods

based on literature review, a survey amongst hospitals in the Netherlands, and our own experience with the establishment of a nationally operating MTB, this paper evaluates current knowledge and unmet needs, and lays out a strategy for successful MTB implementation.

Results

having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, less than 50% of hospitals and only 5% of non-academic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools and workflow. This may not only lead to variation in quality of care, but also hinders data sharing and thus creation of an effective learning community.

Conclusions

this paper acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice, and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member- and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning, but also improve general interpretation and application of genomics-guided cancer care.

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Potential years lost and life expectancy in adults with newly diagnosed epilepsy

Summary

Objective

Studies using relative measures, such as standardized mortality ratios, have shown that patients with epilepsy have an increased mortality. Reports on more direct and absolute measure such as life expectancy are sparse. We report potential years lost and how life expectancy has changed over 40 years in a cohort of patients with newly diagnosed epilepsy.

Methods

We analyzed life expectancy in a cohort of adult patients diagnosed with definite epilepsy between 1970 and 2010. Those with brain tumor as cause of epilepsy were excluded. By retrospective probabilistic record linkage, living or death status was derived from the national death registry. We estimated life expectancy by a Weibull regression model using gender, age at diagnosis, epilepsy etiology, and year of diagnosis as covariates at time of epilepsy diagnosis, and 5, 10, 15, and 20 years after diagnosis. Results were compared to the general population, and 95% confidence intervals are given.

Results

There were 249 deaths (105 women, age at death 19.0–104.0 years) in 1,112 patients (11,978.4 person-years, 474 women, 638 men). A substantial decrease in life expectancy was observed for only a few subgroups, strongly depending on epilepsy etiology and time of diagnosis: time of life lost was highest in patients with symptomatic epilepsy diagnosed between 1970 and 1980; the impact declined with increasing time from diagnosis. Over half of the analyzed subgroups did not differ significantly from the general population. This effect was reversed in the later decades, and life expectancy was prolonged in some subgroups, reaching a maximum in those with newly diagnosed idiopathic and cryptogenic epilepsy between 2001 and 2010.

Significance

Life expectancy is reduced in symptomatic epilepsies. However, in other subgroups, a prolonged life expectancy was found, which has not been reported previously. Reasons may be manifold and call for further study.

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Comparison of Clinical, Radiographic, and Immunologic Inflammatory Parameters around Crestally and Subcrestally Placed Dental Implants: 5-Year Retrospective Results

Abstract

Purpose

To compare changes in clinical (bleeding on probing [BOP] and probing pocket depth [PPD]), radiographic (crestal bone loss [CBL]), and immunologic inflammatory (interleukin-1beta [IL-1β] and matrix metalloproteinase-9 [MMP-9]) parameters around crestally and subcrestally placed dental implants 5 years after implant placement.

Materials and Methods

Fifty-two patients were divided into 2 groups: group 1 (n = 27): patients with single implants placed approximately 2 mm below the alveolar crest; group 2 (n = 25): patients with single implants placed at bone level. In both groups, peri-implant BOP, PPD, and CBL were measured, and levels of IL-1β and MMP-9 were determined in duplicates using enzyme-linked immunosorbent assay. Full-mouth debridement was performed biannually in both groups. Statistical analysis was performed using the Mann-Whitney U test (significance set at p < 0.05).

Results

All measurements in groups 1 and 2 were performed 5.3 ± 0.2 and 5.2 ± 0.1 years after implant placement, respectively. The mean CBL was 1.2 ± 0.2 mm and 1.4 ± 0.2 mm in groups 1 and 2, respectively. There was no significant difference in mean BOP, PPD, CBL and in levels of IL-1β, and MMP-9 among implants in both groups.

Conclusion

Clinical, radiographic, and immunologic inflammatory parameters are comparable around crestally and subcrestally placed single dental implants up to 5 years after placement. The depth of implant placement appears to have no effect on clinical status and performance of single dental implants.

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Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep

Abstract

Background.

We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep.

Methods.

Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets.

Results.

In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol.

Conclusions.

Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation.

Trial registry number.

Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

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Crizotinib targets in glioblastoma stem cells

Abstract

Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non–small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC.

Tissue and stem cells microarrays from nine glioblastomas samples were used to evaluate expression and chromosomal abnormalities of ALK, ROS1, and MET. No molecular rearrangement of these three important genes was observed but rather an overexpression of ALK and MET in some of the glioblastoma stem cell samples, supporting the role of these two genes in tumorigenicity.

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Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Abstract

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC₅₀ values of the Akt inhibitors showed that afuresertib, an ATP-competitive specific Akt inhibitor, exerted tumor-specific effects on MPM cells. Afuresertib significantly increased caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G₁ phase. Western blotting analysis showed that afuresertib increased the expression of p21^WAF1/CIP1 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G₁ phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin-induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM.

Novel ATP-competitive Akt inhibitor afuresertib exerts tumor-specific antiproliferative effect on MPM cells. Afuresertib significantly enhanced cisplatin-induced cytotoxicity, suggesting that afuresertib is a useful anticancer drug for treating patients with MPM.

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Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma

Abstract

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Bone marrow involvement by biopsy complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort, bone marrow involvement by PET/CT could not independently predict a shorter PFS and/or OS.

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The 2016 Al-Mishraq sulphur plant fire: Source and health risk area estimation

Publication date: November 2017
Source:Atmospheric Environment, Volume 169
Author(s): Oscar Björnham, Håkan Grahn, Pontus von Schoenberg, Birgitta Liljedahl, Annica Waleij, Niklas Brännström
On October 20, 2016, Daesh (Islamic State) set fire to the sulphur production site Al-Mishraq as the battle of Mosul in northern Iraq became more intense. An extensive plume of toxic sulphur dioxide and hydrogen sulphide caused comprehensive casualties. The intensity of the SO2 release was reaching levels of minor volcanic eruptions and the plume was observed by several satellites. By investigation of the measurement data from instruments on the MetOp-A, MetOp-B, Aura and Soumi satellites we have estimated the time-dependent source term to 161 kilotonnes sulphur dioxide released into the atmosphere during seven days. A long-range dispersion model was utilized to simulate the atmospheric transport over the Middle East. The ground level concentrations predicted by the simulation were compared with observation from the Turkey National Air Quality Monitoring Network. Finally, the simulation data provided, using a probit analysis of the simulated data, an estimate of the health risk area that was compared to reported urgent medical treatments.

Graphical abstract

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Facing the Future: A Call for Higher Education in Sleep Technology

Publication date: Available online 28 September 2017
Source:Sleep Medicine
Author(s): Laura A. Linley, Richard S. Rosenberg
The American Association of Sleep Technologists (AAST) is the national membership organization representing sleep technologists. The Board of Directors of the AAST recognizes that changes in the workforce will result in an increased need for technologists with a higher level of education. In order to meet the needs of members, the AAST has: (1) convened a summit of stakeholders to discuss the changing landscape for sleep technologists; (2) hosted an educational task force to provide ongoing communication and support; and (3) commissioned a survey of members, educators and employers to better define educational gaps and opportunities for sleep technologists. This report summarizes the results of the survey and provides a roadmap for future educational development. Demographic information highlights the diversity of those in the field of sleep technology. The majority of respondents agree that new technical skills will be needed to achieve competence in sleep technology in the near future, but also that clinical and communication skills will be critical in expanding the role of the sleep technologist in the sleep center. These findings led the AAST leadership to propose new directions for the AAST in serving the needs of its members and the field of sleep technology. This will include a continued focus on education, both basic and advanced, and development of diverse pathways for senior sleep technologists as well as those just entering the field.



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Does length of intubation prior to tracheostomy affect intensive care unit length of stay?

Publication date: Available online 27 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Shaun R. Young, Gary F. Bouloux, Sebastian D. Perez, Shelly Abramowicz
PurposeThe purpose of this study was to determine if length of intubation prior to tracheotomy (LIT) affects length of stay in intensive care unit (ICU).Materials and MethodsThis was a retrospective case series of patients who had open tracheotomies at Grady Memorial Hospital by the Oral and Maxillofacial Surgery (OMS) service. Medical records were reviewed to document patient demographics, etiology for ventilator dependence, and complications. The primary predictor variable was LIT and primary outcome variable was length of stay in ICU after tracheotomy. Statistical analysis was performed (significance p<.05).ResultsThere were 115 subjects (mean age 54 years old) included in the study. Majority received tracheotomies due to prolonged mechanical ventilation secondary to a medical comorbidity. Intraoperative complications were cardiac arrest and difficulty accessing trachea. Postoperative complications were bleeding. Postoperatively, majority of patients were discharged from the ICU or weaned off mechanical ventilation within 5 days. The correlation between LIT and ICU stay was not statistically significant but the trend was positive.ConclusionThe results of this study indicate that patients undergoing an earlier tracheotomy were more likely to have an earlier discharge from the ICU.



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A historical perspective with current opinion on the management of atrophic mandibular fractures

Publication date: Available online 27 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Jaime Castro-Núñez, Larry L. Cunningham, Joseph E. Van Sickels
The management of atrophic mandibular fractures has been a challenge for maxillofacial surgeons for decades. During the past 70 years, various techniques for treating edentulous mandibular fractures have been advocated. These techniques have been praised, critized, abandoned, improved, and used in combination with other methods. Although some of the principles of management outlined before the end of World War II are still valid in today's technological era, other concepts did not survive the test of time. The aim of this paper is to examine the evolution of treatment modalities for the management of atrophic mandibular fractures that have been employed over the years. Debates and discussions generated by this topic are included. Current techniques and treatment philosophies with thoughts for future therapies are provided.



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Long-term disability progression in primary progressive multiple sclerosis: a 15-year study

Abstract

Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T₁-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R² = 61% versus R² = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.

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Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients

Abstract

Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adopted—for the first time—a functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocol—a picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients' naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohen's d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.

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Clinical, pathological and functional characterization of riboflavin-responsive neuropathy

Abstract

Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

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Divergent neural responses to narrative speech in disorders of consciousness

Abstract

Objective

Clinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ intersubject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls.

Methods

Electroencephalographic data were recorded from 20 subjects with disorders of consciousness and 14 healthy controls during of two narrative audio stimuli, presented both forwards and time-reversed. Intersubject correlation of evoked electroencephalography signals were calculated, comparing responses of both groups to those of the healthy control subjects. This analysis was performed blinded and subsequently compared to the diagnostic status of each patient based on the Coma Recovery Scale-Revised.

Results

Subjects with disorders of consciousness exhibit significantly lower intersubject correlation than healthy controls during narrative speech. Additionally, while healthy subjects had higher intersubject correlation values in forwards versus backwards presentation, neural responses did not vary significantly with the direction of playback in subjects with disorders of consciousness. Increased intersubject correlation values in the backward speech condition were noted with improving disorder of consciousness diagnosis, both in cross-sectional analysis and in a subset of patients with longitudinal data.

Interpretation

Intersubject correlation of neural responses to narrative speech audition differentiates healthy controls from patients and appears to index clinical diagnoses in disorders of consciousness.

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Autism-relevant traits interact with temporoparietal junction stimulation effects on social cognition: a high-definition transcranial direct current stimulation and electroencephalography study

Abstract

The temporoparietal junction (TPJ) is implicated in mental and emotional state attribution, processes associated with autism-relevant traits. Transcranial direct current stimulation (tDCS) to the TPJ can influence social-cognitive performance. However, associations with electrophysiology and autism-relevant traits remain relatively unexamined. This study had two aims: first, exploring links between Autism-Spectrum Quotient (AQ) scores and social-cognitive performance; second, examining interactions between AQ scores and high-definition-tDCS (HD-tDCS) applied to the right TPJ in terms of mental/emotional state attribution and neurophysiological outcomes. Fifty-three participants completed mental/emotional state attribution tasks before and after HD-tDCS. Pre-stimulation mental state attribution accuracy was reduced in participants with higher AQ Switching scores. Cathodal stimulation was associated with reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores (the latter at trend-level). Anodal stimulation more frequently interacted with AQ Social scores in terms of neurophysiology, in particular regarding reduced delta power in the left compared to right TPJ, and trend-level positive interactions with P100 and P300 latencies during the emotion recognition task. Elements of attention/switching (AQ Switching) may subserve or underpin elements of social cognition (AQ Social), and cathodal and anodal stimulation may have differing effects depending on trait levels in these domains. This study makes an important and original contribution in terms of increasing understanding of how such trait-level variation might interact with the effects of tDCS and also extending previous studies with regard to understanding potential roles of the rTPJ in both attention and social cognition and how autism-relevant traits might influence TPJ function.

This study examines links between Autism-Spectrum Quotient (AQ) scores and social cognition, and interactions between AQ and rTPJ high-definition-tDCS. Cathodal tDCS reduced emotion attribution performance in participants with higher AQ Switching and AQ Social scores. Anodal tDCS interacted with AQ Social scores, in particular regarding reduced delta power in the lTPJ compared to rTPJ, and trend-level positive interactions with P100 and P300 latencies during emotion attribution. Such trait-level variations interact with tDCS effects on both behaviour and neurophysiology.

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Announcements

Dear Colleagues,

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EACMFS Prizes and Awards

The Council of EACMFS wishes to ensure that all members of the Association are aware of the current awards and prizes that are available. These are designed to provide educational support and also to allow the opportunity for trainees and those who have recently achieved specialist status to visit units outside their own departments.

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Editorial Board

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Procaine and Local Anesthetic Toxicity: A Collaboration Between the Clinical and Basic Sciences.

In 1924, the Therapeutic Research Committee of the American Medical Association appointed a special committee to investigate deaths following the administration of local anesthetics. The Committee for the Study of Toxic Effects of Local Anesthetics found procaine, although a safer clinical alternative to cocaine, was capable of causing death when large doses were injected into tissues and advised that it should be used with caution. This article describes a collaboration beginning in 1928 between Dr John Lundy of the Mayo Clinic and Dr Robert Isenberger of the University of Kansas, which arose from a controversy surrounding systemic adverse reactions to procaine. Isenberger then traveled to the Mayo Clinic to conduct research on various procaine local and spinal anesthesia doses and sodium amytal's protective effect against procaine-induced toxicity. Lundy and Isenberger's work would add to the ongoing discovery of systemic reactions to local anesthetics. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Impact of Regional Anesthesia on Recurrence, Metastasis, and Immune Response in Breast Cancer Surgery: A Systematic Review of the Literature.

Background and Objectives: The perioperative period is critical in the long-term prognosis of breast cancer patients. The use of regional anesthesia, such as paravertebral block (PVB), could be associated with improvements in long-term survival after breast cancer surgery by modulating the inflammatory and immune response associated with the surgical trauma, reducing opioid and general anesthetic consumption, and promoting cancer cells death by a direct effect of local anesthetics. Methods: A systematic literature search was conducted for studies of patients who received PVB for breast cancer surgery. The Jadad score and Ottawa-Newcastle scale were used to assess the methodological quality of randomized controlled trial and observational retrospective studies, respectively. Only high-quality studies were considered for meta-analysis. The selected studies were divided into 3 groups to determine the impact of PVB on (a) recurrence and survival, (b) humoral response, and (c) cellular immune response. Results: We identified 467 relevant studies; 121 of them underwent title and abstract review, 107 were excluded, and 15 studies were selected for full text reading and quality assessment. A meta-analysis was not conducted because of low-quality studies and lack of uniform definition among primary outcomes. Thus, a systematic review of the current evidence was performed. Conclusions: Our study indicates that there are no data to support or refute the use of PVB for reduction of cancer recurrence or improvement in cancer-related survival. However, PVB use is associated with lower levels of inflammation and a better immune response in comparison with general anesthesia and opioid-based analgesia. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Identification of MEK162 as a radiosensitizer for the treatment of glioblastoma

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small molecule drugs including MK2206, RAD001, BEZ235, MLN0128 and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction and time to regrow), cell cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 x 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 down-regulated and dephosphorylated the cell cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation this led to a prolonged DNA damage signal. In vivo data on tumor bearing animals demonstrated a significantly reduced growth rate, increased growth delay and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early phase clinical study in GBM patients.

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Pathway-enriched gene signature associated with 53BP1 response to PARP inhibition in triple-negative breast cancer

Treatment of patients with triple negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients that will most benefit from anti-PARP therapy. We determined the response of three PARP inhibitors: veliparib, olaparib, and talazoparib in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved-PARP). We determined the pharmacodynamic changes in percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved-PARP. Inspired by traditional dose-response measures of cell viability, an EC50 value was calculated for each cellular phenotype for each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients not treated with anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition.

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CRISPR genome-wide screening identifies dependence on the proteasome subunit PSMC6 for Bortezomib sensitivity in multiple myeloma

Bortezomib (BTZ) is highly effective in the treatment of Multiple Myeloma (MM), however emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to BTZ resistance. Specifically, we engineered an RPMI8226 MM cell line to express Cas9 and a lentiviral-vector CRISPR library and cultured derived cells in doses of BTZ lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance. From two independent whole genome screens, we selected 31 candidate genes and constructed a second CRISPR sgRNA library, specifically targeting each of these 31 genes with four sgRNAs. After secondary screening for BTZ resistance, the top 20 "resistance" genes were selected for individual validation. Of these 20 targets the proteasome regulatory subunit PSMC6 was the only gene validated to reproducibly confer BTZ resistance. We confirmed that inhibition of chymotrypsin-like proteasome activity by BTZ was significantly reduced in cells lacking PSMC6. We individually investigated other members of the PSMC group (PSMC1 to 5) and found that deficiency in each of those subunits also imparts BTZ resistance. We found 36 mutations in 19S proteasome subunits out of 895 patients in the IA10 release of the CoMMapss study (http://ift.tt/2xBOiSL). Our findings demonstrate that the PSMC6 subunit is the most prominent target required for BTZ sensitivity in MM cells and should be examined in drug refractory populations.

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Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT CRC, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase (NADK) or ketohexokinase (KHK) were growth inhibitory in vivo. Additionally, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors.

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Gliotransmission and adenosinergic modulation: insights from mammalian spinal motor networks

Astrocytes are proposed to converse with neurons at tripartite synapses, detecting neurotransmitter release and responding with release of gliotransmitters, which in turn modulate synaptic strength and neuronal excitability. However, a paucity of evidence from behavioral studies calls into question the importance of gliotransmission for the operation of the nervous system in healthy animals. Central pattern generator (CPG) networks in the spinal cord and brainstem coordinate the activation of muscles during stereotyped activities such as locomotion, inspiration and mastication, and may therefore provide tractable models in which to assess the contribution of gliotransmission to behaviorally relevant neural activity. Here, we review evidence for gliotransmission within spinal locomotor networks, including studies indicating that adenosine derived from astrocytes regulates the speed of locomotor activity via metamodulation of dopamine signaling.

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Breathing above the brainstem: Volitional control and attentional modulation in humans.

While the neurophysiology of respiration has traditionally focused on automatic brainstem processes, higher brain mechanisms underlying the cognitive aspects of breathing are gaining increasing interest. Therapeutic techniques have used conscious control and awareness of breathing for millennia with little understanding of the mechanisms underlying their efficacy. Using direct intracranial recordings in humans, we correlated cortical and limbic neuronal activity as measured by the intracranial electroencephalogram (iEEG) with the breathing cycle. We show this to be the direct result of neuronal activity, as demonstrated both by the specificity of the finding to the cortical grey matter and the tracking of breath by the gamma band (40-150 Hz) envelope in these structures. We extend prior observations by showing the iEEG signal to track the breathing cycle across a widespread network of cortical and limbic structures. We further demonstrate a sensitivity of this tracking to cognitive factors using tasks adapted from cognitive behavioral therapy and meditative practice. Specifically, volitional control and awareness of breathing engage distinct but overlapping brain circuits. During volitionally-paced breathing, iEEG-breath coherence increases in a fronto-temporal-insular network, and during attention to breathing, we demonstrate increased coherence in the anterior cingulate, premotor, insular and hippocampal cortices. Our findings suggest that breathing can act as an organizing hierarchical principle for neuronal oscillations throughout the brain, and detail mechanisms of how cognitive factors impact otherwise-automatic neuronal processes during interoceptive attention.

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Low-threshold mechanoreceptors play a frequency-dependent, dual role in subjective ratings of mechanical allodynia.

In the setting of injury, myelinated primary afferent fibers that normally signal light touch, are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where increased brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated mechanoreceptor firing activity influenced perception and brain activity (fMRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness, such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing while brushing sensitized skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high and low frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences.

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Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike and wave-like electrographic events in vitro.

Acute In vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike and wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalised and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden and apparent anatomical origin (thalamic, neocortical or both), but any relationship between this heterogeneity and underlying pathology remains elusive. Here we demonstrate that physiological delta frequency rhythms act as an effective substrate to permit modelling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modelled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies.

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Memory-guided saccades show effect of perceptual illusion whereas visually-guided saccades do not

The double-drift stimulus (a drifting Gabor with orthogonal internal motion) generates a large discrepancy between its physical and perceived path. Surprisingly, saccades directed to the double-drift stimulus land along the physical, and not perceived, path (Lisi & Cavanagh, 2015). Here we asked whether memory-guided saccades exhibited the same dissociation from perception. Participants were asked to keep their gaze centered on a fixation dot while the double-drift stimulus moved back and forth on a linear path in the periphery. The offset of the fixation was the go-signal to make a saccade to the target. In the visually-guided saccade condition, the Gabor kept moving on its trajectory after the go-signal but was removed once the saccade began. In the memory conditions, the Gabor disappeared before or at the same time as the go-signal (0 to 1000 ms delay) and participants made a saccade to its remembered location. The results showed that visually-guided saccades again targeted the physical rather than the perceived location. However, memory saccades, even with 0 ms delay, had landing positions shifted toward the perceived location. Our result shows that memory- and visually-guided saccades are based on different spatial information.

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High variability impairs motor learning regardless of whether it affects task performance

Motor variability plays an important role in motor learning, although the exact mechanisms of how variability affects learning is not well understood. Recent evidence suggests that motor variability may have different effects on learning in redundant tasks, depending on whether it is present in the task space (where it affects task performance), or in the null space (where it has no effect on task performance). Here we examined the effect of directly introducing null and task space variability using a manipulandum during the learning of a motor task. Participants learned a bimanual shuffleboard task for 2 days, where their goal was to slide a virtual puck as close as possible towards a target. Critically, the distance traveled by the puck was determined by the sum of the left and right hand velocities, which meant that there was redundancy in the task. Participants were divided into five groups - based on both the dimension in which the variability was introduced and the amount of variability that was introduced during training. Results showed that although all groups were able to reduce error with practice, learning was affected more by the amount of variability introduced rather than the dimension in which variability was introduced. Specifically, groups with higher movement variability during practice showed larger errors at the end of practice compared to groups that had low variability during learning. These results suggest that although introducing variability can increase exploration of new solutions, this may adversely affect the ability to retain the learned solution.

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Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3-:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.

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A phase 1, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth factor receptor mutations

PURPOSE: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. EXPERIMENTAL DESIGN: In this multi-cohort, phase 1 study (NCT02113813), escalating doses of ASP8273 (25-500mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose-escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating-free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. RESULTS: A total of 110 patients were treated with ASP8273 across dose-escalation (n=36), response-expansion (n=36), RP2D (300mg; n=19) and food-effect (n=19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n=27/88, 95% CI 19.5-44.5%), and median progression-free survival was 6.8 months (95% CI 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. CONCLUSIONS: ASP8273 was well-tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy.

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The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma

Purpose. We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynaecological malignancy of poor prognosis. Experimental design. We performed copy number, mutational state and zygosity analysis of 151 genes in SCC arising in MCT (n=25) using next-generation sequencing. The presence of high/intermediate risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome Results. MCT had a low mutation burden with a mean of only 1 mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%) and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8/20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions. Ovarian SCC arising in MCT has a high mutational burden with TP53 mutation the most common abnormality. The presence TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs.

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Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T cell Epitopes & Immune Signatures in a Subset of Prostate Cancer

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events. Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration. Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune-cell infiltration within a sub-group of prostate cancer patients.

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A first-in-human Phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors

Purpose: Wnt signaling is implicated in tumor cell de-differentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental Design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. Objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in 7 dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15 and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related Grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related Grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days, and had low incidence of anti-drug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients.

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Comparison of snoring sounds between natural and drug-induced sleep recorded using a smartphone

Snoring is an important clinical feature of obstructive sleep apnea (OSA), and recent studies suggest that the acoustic quality of snoring sounds is markedly different in drug-induced sleep compared with natural sleep. However, considering differences in sound recording methods and analysis parameters, further studies are required. This study explored whether acoustic analysis of drug-induced sleep is useful as a screening test that reflects the characteristics of natural sleep in snoring patients.

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The Role of Allergy in Chronic Rhinosinusitis

The role of allergy in chronic rhinosinusitis (CRS) has long been debated and remains controversial. The 2 diseases frequently co-occur; however, direct causality has never been proved. The literature is largely mixed as to the manner and degree by which allergy contributes to CRS and this is in large part due to heterogeneity in the definitions of allergy and of CRS. In this review, the potential role of allergy in the disease processes of CRS without polyps, CRS with polyps, and allergic fungal rhinosinusitis is discussed.

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Advances in Food Allergy

Food allergy has been increasing in prevalence for the last few decades, and numerous studies have evaluated ways of improving the allergy practitioner's ability to accurately diagnose patients who are truly food allergic, rather than sensitive but able to tolerate food. Once diagnosed, the current standard treatment is food elimination and avoidance, but other potential treatment options like oral immunotherapy, sublingual immunotherapy, and epicutaneous immunotherapy are becoming promising alternatives. Due the health care costs and potential for life-threatening adverse reactions, much attention has been given to the prevention of food allergies, resulting a shift in recent guideline recommendations.

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Immunotherapy

Polysensitization, sensitization to more than one allergen, is a common feature of patients with allergic rhinitis, and may be a risk factor for subsequent development of allergic diseases, especially allergic asthma. However, a polysensitized patient does not necessarily have polyallergy, a documented, causal relationship between exposure to 2 or more specific, sensitizing allergens and the subsequent occurrence of relevant clinical symptoms of allergy. Allergen immunotherapy treatment strategy for the polysensitized patient in Europe is to treat the single or 2 most clinically relevant allergen(s), whereas patients in the United States are usually treated for all potential clinically relevant allergens.

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