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Background: Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time. Objectives: To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS). Design: National, open, non-interventional, prospective, multicenter study. Methods: TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected. Results: In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients. Conclusion: Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials. Trial registration: Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

Introduction Current ketamine-based therapies for treatment-resistant depression (TRD) often induce dissociative effects. A novel oral PR ketamine formulation (KET01) results in a low and delayed peak concentration of ketamine, high hydroxynorketamine concentration, and is associated with limited dissociative properties. Objectives To investigate efficacy, safety, and pharmacokinetics of KET01 in TRD. Methods KET01-02 was a randomized, double-blind phase 2 trial in outpatients with TRD comparing adjunct 120 mg (n=42) or 240 mg (n=40) oral KET01 once-daily for 3 weeks to placebo (PBO, n=40). The primary endpoint was change from baseline in the MADRS mean score on Day 21. KET01-03 was a randomized, double-blind, cross-over phase I trial in 26 healthy volunteers comparing single doses of 240 mg oral KET01 and 84 mg an approved intranasal formulation of eketamine. The primary endpoint was maximum change of Clinician-Administered Dissociative States Scale (CADSS) score from baseline. Results KET01-03 trial; the mean (±SD) maximum change of CADSS score within 24 hours after dosing was 29.6±12.5 for intranasal eketamine and 0.7±1.7 for KET01 (p4 and increase from baseline. At 7 hours post first KET01 dose (240 mg), plasma concentration of ketamine (38.7±27.0 ng/ml) was lower than its metabolites norketamine (267.5±81.6 ng/ml) and hydroxynorketamine (190.2±85.5 ng/ml). 240 mg/day KET01 induced clinically relevant reduction from baseline in MADRS score already within the first 7 hours of treatment (-7.65; Δ vs PBO: -2.22, n.s.), with a statistically significant separation on Day 4 (-10.02; Δ vs PBO: -3.66, p=0.020) and Day 7 (-12.21; Δ vs PBO: -3.95, p=0.042). MADRS score decrease was sustained throughout Day 21 (-13.15; Δ vs PBO: -1.82, n.s.), and during 4-week follow-up (-12.51; Δ vs PBO: -3.35, n.s.). Treatment-emergent adverse events occurred in 47.5%, 50.0%, and 62.5% of patients in the PBO, 120 mg/day, and 240 mg/day KET01 group, respectively. Conclusions Oral 240 mg/day KET01 induces a rapid, and clinically relevant reduction of depressive symptoms with only minimal signs of dissociation, potentially due to lower ketamine levels and increased norketamine and hydroxynorketamine levels compared to intravenous administration. Our results suggest that KET01 may be an efficacious and safe take-at-home adjunct treatment for TRD. Disclosure of Interest C. zu Eulenburg Employee of: HMNC Brain Health, E. Papanastasiou Employee of: HMNC Brain Health, K. Schmid Employee of: Develco Pharma, A. Damyanova Employee of: HMNC Brain Health, A. Glas Employee of: HMNC Brain Health, C. Strote Employee of: HMNC Brain Health, L. Arvastson Employee of: HMNC Brain Health, H. Eriksson Employee of: HMNC Brain Health

IntroductionThe negative impact of unmanaged psychological distress on quality of life and outcome in breast cancer survivors has been demonstrated. Fortunately, studies indicate that distress can effectively be addressed and even prevented using evidence-based interventions. In Germany prescription-based mobile health apps, known as DiGAs (digital health applications), that are fully reimbursed by health insurances, were introduced in 2020. In this study, the effectiveness of an approved breast cancer DiGA was investigated: The personalized coaching app PINK! Coach supports and accompanies breast cancer patients during therapy and follow-up.MethodsPINK! Coach was specifically designed for breast cancer (BC) patients from the day of diagnosis to the time of Follow-up (aftercare). The app offers individualized, evidence-based therapy and side-effect management, mindfulness-based stress reduction, nutritional and psychological education, physical activity tracking, and motivational exercises to implement lifestyle changes sustainably in daily routine. A prospective, intraindividual RCT (DRKS00028699) was performed with n = 434 patients recruited in 7 German breast cancer centers from September 2022 until January 2023. Patients with BC were included independent of their stage of diseases, type of therapy and molecular characteristics of the tumor. Patients were randomized into one of two groups: The intervention group got access to PINK! over 12 weeks; the control group served as a waiting-list comparison to “standard of care.” The primary endpoint was psychological distress objectified by means of Patient Health Questionnaire-9 (PHQ-9). Subgroups were defined to investigate the app’s effect on several patient groups such as MBC vs. EBC patients, patients on therapy vs. in aftercare, patients who received a chemotherapy vs. patients who did not.ResultsEfficacy analysis of the primary endpoint revealed a significant reduction in psychological distress (least squares estimate -1.62, 95% confidence interval [1.03; 2.21]; p

Abstract Space exploration objectives will soon move from low Earth orbit to distant destinations like Moon and Mars. The present work provides an up-to-date roadmap that identifies critical research gaps related to human behavior and performance in altered gravity and space. The roadmap summarizes (1) key neurobehavioral challenges associated with spaceflight, (2) the need to consider sex as a biological variable, (3) the use of integrative omics technologies to elucidate mechanisms underlying changes in the brain and behavior, and (4) the importance of understanding the neural representation of gravity throughout the brain and its multisensory processing. We then highlight the need for a variety of target-specific countermeasures, and a personalized administration schedule as two critical strategies for mitigating potentially adverse effects of spaceflight on the central nervous system and performance. We conclude with a summary of key priorities for the roadmaps of current and future space programs and stress the importance of new collaborative strategies across agencies and researchers for fostering an integrative cross- and transdisciplinary approach from cells, molecules to neural circuits and cognitive performance. Finally, we highlight that space research in neurocognitive science goes beyond monitoring and mitigating risks in astronauts but could also have significant benefits for the population on Earth.

Abstract Long-duration human spaceflight can lead to changes in both the eye and the brain, which have been referred to as Spaceflight Associated Neuro-ocular Syndrome (SANS). These changes may manifest as a constellation of symptoms, which can include optic disc edema, optic nerve sheath distension, choroidal folds, globe flattening, hyperopic shift, and cotton wool spots. Although the underpinning mechanisms for SANS are not yet known, contributors may include intracranial interstitial fluid accumulation following microgravity induced headward fluid shift. Development and validation of SANS countermeasures contribute to our understanding of etiology and accelerate new technology including exercise modalities, Lower Body Negative Pressure suits, venous thigh cuffs, and Impedance Threshold Devices. However, significant knowledge gaps remain including biomarkers, a full set of countermeasures and/or treatment regimes, and finally reliable ground based analogs to accelerate the research. This review from the European Space Agency SANS expert group summarizes past research and current knowledge on SANS, potential countermeasures, and key knowledge gaps, to further our understanding, prevention, and treatment of SANS both during human spaceflight and future extraterrestrial surface exploration.

In addition to general anesthesia and mechanical ventilation, robotic-assisted laparoscopic radical prostatectomy (RALP) necessitates maintaining a capnoperitoneum and placing the patient in a pronounced downward tilt (Trendelenburg position). While the effects of the resulting fluid shift on the cardiovascular system seem to be modest and well tolerated, the effects on the brain and the blood–brain barrier have not been thoroughly investigated. Previous studies indicated that select patients showed an increase in the optic nerve sheath diameter (ONSD), detected by ultrasound during RALP, which suggests an elevation in intracranial pressure. We hypothesize that the intraoperative fluid shift results in endothelial dysfunction and reduced cerebral clearance, potentially leading to transient neuronal damage. This prospective, monocentric, non-randomized, controlled clinical trial will compare RALP to conventional open radical prostatectomy (control group) in a total of 50 subjects. The primary endpoint will be the perioperative concentration of neurofilament light chain (NfL) in blood using single-molecule array (SiMoA) as a measure for neuronal damage. As secondary endpoints, various other markers for endothelial function, inflammation, and neuronal damage as well as the ONSD will be assessed. Perioperative stress will be evaluated by questionnaires and stress hormone levels in saliva samples. Furthermore, the subjects will participate in functional tests to evaluate neurocognitive function. Each subject will be followed up until discharge. Conclusion: This trial aims to expand current knowledge as well as to develop strategies for improved monitoring and higher safety of patients undergoing RALP. The trial was registered with the German Clinical Trials Register DRKS00031041 on 11 January 2023.

rs-fMRI is used to investigate human brain connectivity changes induced by prolonged microgravity in cosmonauts before and after spaceflight, with both persistent and reversible location specific changes in connectivity being observed.

Objective: We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials. Methods: US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders. Results: pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45–5.29, and OR 4.17, 95%CI 2.26–7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08–1.24, and OR 1.25, 95%CI 1.16–1.35, respectively) as parameters associated with pCR. Conclusions: Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria.

All volitional movement in a three-dimensional space requires multisensory integration, in particular of visual and vestibular signals. Where and how the human brain processes and integrates self-motion signals remains enigmatic. Here, we applied visual and vestibular self-motion stimulation using fast and precise whole-brain neuroimaging to delineate and characterize the entire cortical and subcortical egomotion network in a substantial cohort (n=131). Our results identify a core egomotion network consisting of areas in the cingulate sulcus (CSv, PcM/pCi), the cerebellum (uvula), and the temporo-parietal cortex including area VPS and an unnamed region in the supramarginal gyrus. Based on its cerebral connectivity pattern and anatomical localization, we propose that this region represents the human homologue of macaque area 7a. Whole-brain connectivity and gradient analyses imply an essential role of the connections between the cingulate sulcus and the cerebellar uvula in egomotion perception. This could be via feedback loops involved updating visuo-spatial and vestibular information. The unique functional connectivity patterns of PcM/pCi hint at central role in multisensory integration essential for the perception of self-referential spatial awareness. All cortical egomotion hubs showed modular functional connectivity with other visual, vestibular, somatosensory and higher order motor areas, underlining their mutual function in general sensorimotor integration.

A team of experts on the effects of the spaceflight environment on the brain and eye (SANS: Spaceflight-Associated Neuro-ocular Syndrome) was convened by NASA and ESA to (1) review spaceflight-associated structural and functional changes of the human brain and eye, and any interactions between the two; and (2) identify critical future research directions in this area to help characterize the risk and identify possible countermeasures and strategies to mitigate the spaceflight-induced brain and eye alterations. The experts identified 14 critical future research directions that would substantially advance our knowledge of the effects of spending prolonged periods of time in the spaceflight environment on SANS, as well as brain structure and function. They used a paired comparison approach to rank the relative importance of these 14 recommendations, which are discussed in detail in the main report and are summarized briefly below.

Background: The potential benefit of additional breast cancer screening examinations in moderate risk patients (patients with a history of breast cancer in one or two family members) remains unclear. Methods: A large population-based case–control study on breast cancer in postmenopausal women in Germany recruited 2002–2005 (3813 cases and 7341 age-matched controls) was used to assess the association of family history with breast cancer risk. Analysis of family history, participation in screening procedures, and tumor size regarding prognosis in patients was based on follow-up data until 2015. Results: A first degree family history of breast cancer was associated with higher breast cancer risk (OR 1.39, p 10 mammograms (MG) (42.7% vs. 24.9%, p

Abstract Brain atlases and templates are core tools in scientific research with increasing importance also in clinical applications. Advances in neuroimaging now allowed us to expand the atlas domain to the vestibular and auditory organ, the inner ear. In this study, we present IE-Map, an in-vivo template and atlas of the human labyrinth derived from multi-modal high-resolution magnetic resonance imaging (MRI) data, in a fully non-invasive manner without any contrast agent or radiation. We reconstructed a common template from 126 inner ears (63 normal subjects) and annotated it with 94 established landmarks and semi-automatic segmentations of all relevant macroscopic vestibular and auditory substructures. We validated the atlas by comparing MRI templates to a novel CT/micro-CT atlas, which we reconstructed from 21 publicly available post-mortem images of the bony labyrinth. Templates in MRI and micro-CT have a high overlap, and several key anatomical measures of the bony labyrinth in IE-Map are in line with micro-CT literature of the inner ear. A quantitative substructural analysis based on the new template, revealed a correlation of labyrinth parameters with total intracranial volume. No effects of gender or laterality were found. We provide the validated templates, atlas segmentations, surface meshes and landmark annotations as open-access material, to provide neuroscience researchers and clinicians in neurology, neurosurgery, and otorhinolaryngology with a widely applicable tool for computational neuro-otology.

Abstract Objective Patients with acute central vestibular syndrome suffer from vertigo, spontaneous nystagmus, postural instability with lateral falls, and tilts of visual vertical. Usually, these symptoms compensate within months. The mechanisms of compensation in vestibular infarcts are yet unclear. This study focused on structural changes in gray and white matter volume that accompany clinical compensation. Methods We studied patients with acute unilateral brain stem infarcts prospectively over 6 months. Structural changes were compared between the acute phase and follow‐up with a group of healthy controls using voxel‐based morphometry. Results Restitution of vestibular function following brain stem infarcts was accompanied by downstream structural changes in multisensory cortical areas. The changes depended on the location of the infarct along the vestibular pathways in patients with pathological tilts of the SVV and on the quality of the vestibular percept (rotatory vs graviceptive) in patients with pontomedullary infarcts. Patients with pontomedullary infarcts with vertigo or spontaneous nystagmus showed volumetric increases in vestibular parietal opercular multisensory and (retro‐) insular areas with right‐sided preference. Compensation of graviceptive deficits was accompanied by adaptive changes in multiple multisensory vestibular areas in both hemispheres in lower brain stem infarcts and by additional changes in the motor system in upper brain stem infarcts. Interpretation This study demonstrates multisensory neuroplasticity in both hemispheres along with the clinical compensation of vestibular deficits following unilateral brain stem infarcts. The data further solidify the concept of a right‐hemispheric specialization for core vestibular processing. The identification of cortical structures involved in central compensation could serve as a platform to launch novel rehabilitative treatments such as transcranial stimulations.

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways.

Objective: The integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. Methods: Thirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. Results: Patients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. Conclusions: White matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Objective: Structural reorganization following cerebellar infarcts is not yet known. This study aimed to demonstrate structural volumetric changes over time in the cortical vestibular and multisensory areas (i.e., brain plasticity) after acute cerebellar infarcts with vestibular and ocular motor symptoms. Additionally, we evaluated whether structural reorganization in the patients topographically correlates with cerebello-cortical connectivity that can be observed in healthy participants. Methods: We obtained high-resolution structural imaging in seven patients with midline cerebellar infarcts at two time points. These data were compared to structural imaging of a group of healthy age-matched controls using voxel-based morphometry (2×2 ANOVA approach). The maximum overlap of the infarcts was used as a seed region for a separate resting-state functional connectivity analysis in healthy volunteers. Results: Volumetric changes were detected in the multisensory cortical vestibular areas around the parieto-opercular and (retro-) insular cortex. Furthermore, structural reorganization was evident in parts of the frontal, temporal, parietal, limbic, and occipital lobes and reflected functional connections between the main infarct regions in the cerebellum and the cerebral cortex in healthy individuals. Conclusions: This study demonstrates structural reorganization in the parieto-opercular insular vestibular cortex after acute vestibulo-cerebellar infarcts. Additionally, the widely distributed structural reorganization after midline cerebellar infarcts provides additional in vivo evidence for the multifaceted contribution of cerebellar processing to cortical functions that extend beyond vestibular or ocular motor function.

Background: Little is known about the cortical organization of human vestibular information processing. Instead of a dedicated primary vestibular cortex, a distributed network of regions across the cortex respond to vestibular input. The aim of this study is to characterize the human corticocortical vestibular network and compare it to established results in non-human primates. Methods: We collected high-resolution multi-shell diffusion-weighted (DWI) and state-of-the-art resting-state functional MR images of 29 right-handed normal subjects. Ten cortical vestibular regions per hemisphere were predefined from previous vestibular stimulation studies and applied as regions of interest. Four different structural corticocortical vestibular networks accounting for relevant constraints were investigated. The analyses included the investigation of common network measures and hemispheric differences for functional and structural connectivity patterns alike. In addition, the results of the structural vestibular network were compared to findings previously reported in non-human primates with respect to tracer injections (Guldin and Grusser, 1998). Results: All structural networks independent of the applied constraints showed a recurring subdivision into identical three submodules. The structural human network was characterized by a predominantly intrahemispheric connectivity, whereas the functional pattern highlighted a strong connectivity for all homotopic nodes. A significant laterality preference towards the right hemisphere can be observed throughout the analyses: (1) with larger nodes, (2) stronger connectivity values structurally and functionally, and (3) a higher functional relevance. Similar connectivity patterns to non-human primate data were found in sensory and higher association cortices rather than premotor and motor areas. Conclusion: Our analysis delineated a remarkably stable organization of cortical vestibular connectivity. Differences found between primate species may be attributed to phylogeny as well as methodological differences. With our work we solidified evidence for lateralization within the corticocortical vestibular network. Our results might explain why cortical lesions in humans do not lead to persistent vestibular symptoms. Redundant structural routing throughout the network and a high-degree functional connectivity may buffer the network and reestablish network integrity quickly in case of injury.

Mensen met downsyndroom hebben een bijzonder hoog risico op dementie. Desondanks is er weinig bekend over dementiegerelateerde gedragsveranderingen bij mensen met downsyndroom. Een nieuwe evaluatieschaal is ontwikkeld om de aard, frequentie en ernst van gedragsveranderingen in kaart te brengen (83 gedragsitems in 12 klinisch-gedefinieerde secties). Centraal stond het identificeren van items die veranderen in relatie tot de dementiestatus. Gestructureerde interviews zijn gehouden met informanten van mensen met downsyndroom zonder dementie (DS, N = 149), met twijfelachtige dementie (DS + TDN, = 65) en met gediagnosticeerde dementie (DS + ADN, = 67). Groepsvergelijkingen toonden een uitgesproken toename in frequentie en ernst van items over angst, slaapproblemen, agitatie & stereotiep gedrag, agressie, apathie, depressieve kenmerken en eet- en drinkgedrag. Het aantal mensen dat een toename liet zien was procentueel het hoogst in de DS + AD groep en het laagst in de DS groep. Een aanzienlijk percentage van de DS + TD groep vertoonde al een toename in angst, slaapproblemen, apathie en depressieve kenmerken, wat erop duidt dat dit mogelijk vroege alarmsignalen zijn van dementie. De schaal zou kunnen bijdragen aan een beter begrip van de veranderingen, het aanpassen van de dagelijkse zorg/begeleiding, en het bieden van passende behandelingen aan mensen met downsyndroom. Gebaseerd op de resultaten en praktijkervaringen moet de schaal worden verbeterd en moet de toepasbaarheid, betrouwbaarheid en validiteit nog verder onderzocht worden.

The role of different receptors in natural-killer- (NK-) cell-mediated cytotoxicity against multiple myeloma (MM) cells is unknown. We investigated if an enhancement of NK-cell-mediated cytotoxicity against MM could be reached by blocking of the inhibitory leukocyte immunoglobulin-like receptor 1 (LIR-1). Our investigations revealed high levels of LIR-1 expression not only on the NK cell line NK-92, but also on myeloma cells (MOLP-8, RPMI8226) as well as on a lymphoblastoid cell line (LBCL; IM-9). Subsequent cytotoxicity assays were designed to show the isolated effects of LIR-1 blocking on either the effector or the tumor side to rule out receptor-receptor interactions. Although NK-92 was shown to be capable of myeloma cell lysis, inhibition of LIR-1 on NK-92 did not enhance cytotoxicity. Targeting the receptor on MM and LBCL did not also alter NK-92-mediated lysis. We come to the conclusion that LIR-1 alone does not directly influence NK-cell-mediated cytotoxicity against myeloma. To our knowledge, this work provides the first investigation of the inhibitory capability of LIR-1 in NK-92-mediated cytotoxicity against MM and the first functional evaluation of LIR-1 on MM and LBCL.

We assessed the value of breast ultrasound (US) performed at week 3 and 6 and at the end (EOT) of neoadjuvant therapy (NAT) for prediction of pathologic complete response (pCR, ypT0/is ypN0) in patients with HR+/HER2+, HR-/HER2-or HR-/HER2+ early breast cancer enrolled in the WSG-ADAPT subtrials. US was performed at week 3 and 6 of NAT and at EOT in 401, 517, and 553 patients, respectively. Tumors with complete or partial response by US (RECIST 1.1) were classified as responders and those with stable or progressive disease as non-responders. pCR rate was higher in US responders than in non-responders. US tended to yield the highest positive predictive value in HR-/HER2+ (69%) and HR-/HER2-tumors (65%) at week 3, and the highest negative predictive value in HR+/HER2+ tumors at week 6 and at EOT (88.9% and 86.9%, respectively) and in HR-/HER2-tumors at EOT (87.9%). Multivariable analysis of patients with US at week 3 and 6 identified tumor subtype (HR-/HER2+ vs HR+/HER2+; odds ratio (OR) 2.77, 95%CI 1.45–5.29, and OR 4.17, 95%CI 2.26–7.68, respectively) and each 10% change in lesion dimension on US from baseline (OR 1.15, 95%CI 1.08–1.24, and OR 1.25, 95%CI 1.16–1.35, respectively) as parameters associated with pCR. Our data support the use of week 3 and EOT US for prediction of pCR in response-guided NAT and in planning of breast-conserving surgery. Change in tumor diameter on US as a continuous variable could be a valuable alternative to categorical RECIST 1.1 criteria. • Timing of ultrasound may affect prediction of pathologic complete response (pCR). • Ultrasound predicts pCR in HR-tumors as early as at week 3 of neoadjuvant therapy. • Ultrasound predicts non-pCR in HR+/HER2+ tumors at week 6 of neoadjuvant therapy. • Early pCR prediction by ultrasound allows response-guided therapy in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Earlier functional imaging studies on visually induced self-motion perception (vection) disclosed a bilateral network of activations within primary and secondary visual cortex areas which was combined with signal decreases, i.e., deactivations, in multisensory vestibular cortex areas. This finding led to the concept of a reciprocal inhibitory interaction between the visual and vestibular systems. In order to define areas involved in special aspects of self-motion perception such as intensity and duration of the perceived circular vection (CV) or the amount of head tilt, correlation analyses of the regional cerebral glucose metabolism, rCGM (measured by fluorodeoxyglucose positron-emission tomography, FDG-PET) and these perceptual covariates were performed in 14 healthy volunteers. For analyses of the visual-vestibular interaction, the CV data were compared to a random dot motion stimulation condition (not inducing vection) and a control group at rest (no stimulation at all). Results Group subtraction analyses showed that the visual-vestibular interaction was modified during CV, i.e., the activations within the cerebellar vermis and parieto-occipital areas were enhanced. The correlation analysis between the rCGM and the intensity of visually induced vection, experienced as body tilt, showed a relationship for areas of the multisensory vestibular cortical network (inferior parietal lobule bilaterally, anterior cingulate gyrus), the medial parieto-occipital cortex, the frontal eye fields and the cerebellar vermis. The “earlier” multisensory vestibular areas like the parieto-insular vestibular cortex and the superior temporal gyrus did not appear in the latter analysis. The duration of perceived vection after stimulus stop was positively correlated with rCGM in medial temporal lobe areas bilaterally, which included the (para-)hippocampus, known to be involved in various aspects of memory processing. The amount of head tilt was found to be positively correlated with the rCGM of bilateral basal ganglia regions responsible for the control of motor function of the head. Conclusions Our data gave further insights into subfunctions within the complex cortical network involved in the processing of visual-vestibular interaction during CV. Specific areas of this cortical network could be attributed to the ventral stream (“what” pathway) responsible for the duration after stimulus stop and to the dorsal stream (“where/how” pathway) responsible for intensity aspects.