Feasibility of Proton Beam Therapy for Infants with Brain Tumours: Experiences from the Prospective KiProReg Registry Study.

AIMS: Proton beam therapy (PBT) has increasingly been applied for the treatment of young children when radiotherapy is needed. The treatment requires intensive multimodality care and is logistically demanding. In this analysis, we evaluated our experiences in treating infants with tumours of the central nervous system with PBT. MATERIALS AND METHODS: Children younger than 2 years of age treated with PBT for central nervous system tumours enrolled in the prospective registry study KiProReg were retrospectively analysed. Information on patient characteristics, treatment, toxicities and outcome were evaluated. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.0) before, during and after PBT. RESULTS: Between September 2013 and June 2018, 51 infants were eligible. The median age was 19 months (range 11-23 months) at the time of PBT. Tumour entities were ependymoma (51.0%), atypical teratoid rhabdoid tumour (39.0%), high-grade glioma (6.0%), pineoblastoma (2.0%) and medulloblastoma (2.0%). The prescribed median total dose was 54.0 Gy (range 45.0-59.4 Gy). Most received local radiotherapy. In four patients, craniospinal irradiation followed by a boost to the local tumour bed was applied. The median follow-up time was 42.0 months (range 7.3-86.2 months). The estimated 3-year local control, progression-free survival and overall survival rates for all patients were 62.7, 47.1 and 76.5%, respectively. During radiotherapy, 24 events of higher-grade (CTCAE ≥ °III) toxicities were reported. Interruption of radiotherapy for more than 2 days was due to infection (n = 3) or shunt complication (n = 2). Unexpected hospitalisation during radiotherapy affected 12 patients. Late adverse events attributable to radiotherapy included endocrinopathy (CTCAE °II; 7.8%), new onset of hearing loss (CTCAE °III; 5.8%) and visual impairment (CTCAE °IV; 1.9%). Transient radiation-induced imaging changes occurred in five patients (9.8%). CONCLUSIONS: Our study indicates that PBT is feasible for very young children with central nervous system tumours, at least in the short term. However, it requires challenging interdisciplinary medical care and high logistical effort. For evaluation of late effects, longer follow-up and evaluation of neurocognitive outcome are desirable. More data have to be gathered to further define the role of radiotherapy in infants over time.

[From external assessment of pain to automated multimodal measurement of pain intensity : Narrative review of state of research and clinical perspectives]. / Von der Fremdbeurteilung des Schmerzes zur automatisierten multimodalen Messung der Schmerzintensität : Narrativer Review zum Stand der Forschung und zur klinischen Perspektive.

BACKGROUND: In patients with limited communication skills, the use of conventional scales or external assessment is only possible to a limited extent or not at all. Multimodal pain recognition based on artificial intelligence (AI) algorithms could be a solution. OBJECTIVE: Overview of the methods of automated multimodal pain measurement and their recognition rates that were calculated with AI algorithms. METHODS: In April 2018, 101 studies on automated pain recognition were found in the Web of Science database to illustrate the current state of research. A selective literature review with special consideration of recognition rates of automated multimodal pain measurement yielded 14 studies, which are the focus of this review. RESULTS: The variance in recognition rates was 52.9-55.0% (pain threshold) and 66.8-85.7%; in nine studies the recognition rate was ≥80% (pain tolerance), while one study reported recognition rates of 79.3% (pain threshold) and 90.9% (pain tolerance). CONCLUSION: Pain is generally recorded multimodally, based on external observation scales. With regard to automated pain recognition and on the basis of the 14 selected studies, there is to date no conclusive evidence that multimodal automated pain recognition is superior to unimodal pain recognition. In the clinical context, multimodal pain recognition could be advantageous, because this approach is more flexible. In the case of one modality not being available, e.g., electrodermal activity in hand burns, the algorithm could use other modalities (video) and thus compensate for missing information.

[Multimodal recognition of pain intensity and pain modality with machine learning]. / Multimodale Erkennung von Schmerzintensität und -modalität mit maschinellen Lernverfahren.

BACKGROUND: The objective recording of subjectively experienced pain is a problem that has not been sufficiently solved to date. In recent years, data sets have been created to train artificial intelligence algorithms to recognize patterns of pain intensity. The multimodal recognition of pain with machine learning could provide a way to reduce an over- or undersupply of analgesics, explicitly in patients with limited communication skills. OBJECTIVES: This study investigated the methodology of automated multimodal recognition of pain intensity and modality using machine-learning techniques of artificial intelligence. Multimodal recognition rates of experimentally induced phasic electrical and heat pain stimuli were compared with uni- and bimodal recognition rates. MATERIAL AND METHODS: On the basis of the X­ITE Pain Database, healthy subjects were stimulated with phasic electro-induced pain and heat pain, and their corresponding pain responses were recorded with multimodal sensors (acoustic, video-based, physiological). After complex signal processing, machine-learning methods were used to calculate recognition rates with respect to pain intensity (baseline vs. pain threshold, pain tolerance, mean value of pain threshold and tolerance) and pain modality (electrical vs. heat). Finally, a statistical comparison of uni- vs. multimodal and bi- vs. multimodal detection rates was performed. RESULTS: With few exceptions, multimodal recognition of pain intensity rates was statistically superior to unimodal recognition rates, regardless of the pain modality. Multimodal pain recognition distinguished significantly better between heat and electro-induced pain. Further, multimodal recognition rates were predominantly superior to bimodal recognition rates. CONCLUSION: Priority should be given to the multimodal approach to the recognition of pain intensity and modality compared with unimodality. Further clinical studies should clarify whether multimodal automated recognition of pain intensity and modality is in fact superior to bimodal recognition.

[Fibromyalgia syndrome: considerable pain reduction after moving to a "safe site"]. / Fibromyalgiesyndrom: erhebliche Schmerzreduktion nach Wohnungswechsel an einen "sicheren Ort".

A patient with long-term fibromyalgia syndrome and concomitant post-traumatic stress disorder is reported. The relocation to a so-called external safe site resulted within a very short time in a sustained remission of the fibromyalgia syndrome, due to psychotherapeutic interventions. This shows that-according to the clinical guidelines-a psychiatric examination and, if necessary, targeted therapy of the psychiatric comorbidity is indispensable in patients with fibromyalgia syndrome.

[Development through encounter-Kurt Goldstein's contributions to psychotherapy]. / Entwicklung durch Begegnung ­ Kurt Goldsteins Beiträge zur Psychotherapie.

The life and works of neurologist and psychiatrist Kurt Goldstein (1878-1965) were almost forgotten for decades but have aroused increasing interest in recent years. Studies on Goldstein generally focus on his groundbreaking contributions to a holistic neurology, neuropsychology and neurorehabilitation; however, his contributions to the development of psychotherapy have received less attention. The present article reviews Goldstein's substantial input to the development of psychotherapy, and especially of humanistic psychotherapies. It is further shown how these contributions are rooted in Goldstein's observations on brain-damaged World War I veterans. From these observations Goldstein derived a holistic view of the organism as a system that embodies and constantly re-establishes an identity, thereby also defining the meaning of anxiety for human existence and drawing conclusions for the therapeutic relationship. It can therefore be argued that brain research impinged on the development of psychotherapy at an early stage, even though its research paradigm differed profoundly from that of present day reductionism.

Do independent geriatric outpatients with nocturnal polyuria profit from desmopressin?

OBJECTIVE: To compare the efficacy of desmopressin and placebo in independent geriatric outpatients with nocturnal polyuria (NP). METHODS: A prospective, randomized, single-center, national, double blind, placebo-controlled, fixed-dose, parallel group comparative trial was carried out. The study included 110 geriatric outpatients, 55 patients per treatment group using desmopressin acetate nasal spray (strength: 0.1 mg/ml) once daily of 10 µg/spray blast or placebo. MEASUREMENT: The NP positive geriatric outpatients with >33% nocturnal urine output volume, antidiuretic hormone (ADH) positive or negative were treated over 10 days with intranasal spray in the evening time (7 p.m.), drug or placebo. On day 1 voiding frequency, voiding volumes day and night, serum osmolarity and arginine-vasopressin (AVP) were measured at 7 p.m. On days 2, 5 and 10 creatinine, blood urea nitrogen (bun), blood count and C­reactive protein (CrP), vena cava diameter and bioimpedance were measured and a structured interview was implemented (voiding frequency, sleeping behavior and subjective and cognitive behavior). RESULTS: The NP patients showed a mean night voiding volume of 50.60%, 39.21% (n = 102) showed a low AVP level at baseline with no correlation to sodium concentration or voiding frequencies. The primary efficacy criterion, a decrease of the nocturnal voiding frequency during the course of the clinical trial as change from baseline at day 10 (visit 4) was 50% versus 41.40% in the verum versus placebo group, respectively but the differences were not significant. The U­test showed superiority of AVP-positive NP patients to a positive reaction on desmopressin. Sleeping time hours increased in both groups without significant differences. CONCLUSION: In this 10-day clinical trial desmopressin was not proven to be therapeutically superior to placebo with respect to micturition frequency or sleeping hours. Independent geriatric outpatients with decreased ADH levels seemed to respond and benefit from active treatment with desmopressin. The unexpected results in the placebo group may be due to the effect of intensive outpatient care and information on NP outpatients with normal AVP levels.

Roles of Grainyhead-like transcription factors in cancer.

The mammalian homologs of the D. melanogaster Grainyhead gene, Grainyhead-like 1-3 (GRHL1, GRHL2 and GRHL3), are transcription factors implicated in wound healing, tubulogenesis and cancer. Their induced target genes encode diverse epithelial cell adhesion molecules, while mesenchymal genes involved in cell migration and invasion are repressed. Moreover, GRHL2 suppresses the oncogenic epithelial-mesencyhmal transition, thereby acting as a tumor suppressor. Mechanisms, some involving established cancer-related signaling/transcription factor pathways (for example, Wnt, TGF-ß, mir200, ZEB1, OVOL2, p63 and p300) and translational implications of the Grainyhead proteins in cancer are discussed in this review article.

The Evolving Role of Proton Beam Therapy for Sarcomas.

As an alternative to conventional photon-based radiotherapy, radiation with protons is recognised to offer considerable advantages. Today, central nervous system tumours, various sarcomatous tumours, childhood cancer and head and neck tumours are commonly treated with proton therapy. This review evaluates current data from clinical and dosimetric trials on the treatment of selected sarcomatous tumours like rhabdomyosarcoma, osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma. Special considerations for paediatric tumours and future prospects of proton therapy are outlined. Proton therapy is already an internal part in the multidisciplinary management of childhood sarcomas in contiguity to sensitive structures, especially at the base of skull, spine and pelvis. It offers special advantages for tumours requiring high-precision radiotherapy, particularly when total resection seems not feasible. Previous and ongoing research is generating evidence for the benefit of protons in sarcoma patients. Up to now, proton therapy has been safely applied with encouraging results. For future research, prospective, multi-institutional, large registries are required to answer open questions. Modern radiotherapy techniques, such as pencil beam scanning and intensity modulation are increasingly established in proton therapy. More research is needed to understand protons' limitations and potential.

Post-Surgical Language Reorganization Occurs in Tumors of the Dominant and Non-Dominant Hemisphere.

PURPOSE: Surgical resection of brain tumors may shift the location of cortical language areas. Studies of language reorganization primarily investigated left-hemispheric tumors irrespective of hemispheric language dominance. We used functional magnetic resonance imaging (fMRI) to investigate how tumors influence post-surgical language reorganization in relation to the dominant language areas. METHODS: A total of, 17 patients with brain tumors (16 gliomas, one metastasis) in the frontotemporal and lower parietal lobes planned for awake surgery underwent pre-surgical and post-surgical language fMRI. Language activation post-to-pre surgery was evaluated visually and quantitatively on the statistically thresholded images on patient-by-patient basis. Results were qualitatively compared between three patient groups: temporal, with tumors in the dominant temporal lobe, frontal, with tumors in the dominant frontal lobe and remote, with tumors in the non-dominant hemisphere. RESULTS: Post-to-pre-surgical distributions of activated voxels changed in all except the one patient with metastasis. Changes were more pronounced in the dominant hemisphere for all three groups, showing increased number of activated voxels and also new activation areas. Tumor resection in the dominant hemisphere (frontal and temporal) shifted the activation from frontal towards temporal, whereas tumor resection in the non-dominant hemisphere shifted the activation from temporal towards frontal dominant areas. CONCLUSION: Resection of gliomas in the dominant and in the non-dominant hemisphere induces postsurgical shifts and increase in language activation, indicating that infiltrating gliomas have a widespread influence on the language network. The dominant hemisphere gained most of the language activation irrespective of tumor localization, possibly reflecting recovery of pre-surgical tumor-induced suppression of these activations.

Pyoderma gangrenosum and pregnancy: an example of abnormal inflammation and challenging treatment.

Pyoderma gangrenosum (PG) is a neutrophil-predominant inflammatory disease that initially presents as a sterile pustule and may progress to ulcerations. Its root cause is unknown, but the presentation is commonly associated with systemic inflammatory conditions such as inflammatory bowel disease, arthritis and haematological abnormalities. On the other hand, pregnant women show a progressive neutrophilia during gestation, which culminates in a major inflammatory event to help drive labour. Although uncommonly, PG has been associated with pregnancy, which provides an additional link to systemic inflammation as an underlying cause of PG. We reviewed documented presentations of PG in gravid and post-partum patients, and have speculated on the possible pathogenesis based on their clinical presentations. Also, we summarize the reported treatments and their outcomes in these patients.

Individual differences in common factors of emotional traits and executive functions predict functional connectivity of the amygdala.

Evidence suggests that individual differences in emotion control are associated with frontoparietal-limbic networks and linked to emotional traits and executive functions. In a first attempt to directly target the link between emotional traits and executive functions using resting-state fMRI analysis, 43 healthy adults completed a test battery including executive tasks and emotional trait self-assessments that were subjected to a principal component analysis. Of the three factors detected, two explained 40.4% of the variance and were further investigated. Both factors suggest a relation between emotional traits and executive functions. Specifically, the first factor consisted of measures related to inhibitory control and negative affect, and the second factor was related to reward and positive affect. To investigate whether this interplay between emotional traits and executive functions is reflected in neural connectivity, we used resting-state fMRI to explore the functional connectivity of the amygdala as a starting point, and progressed to other seed-based analyses based on the initial findings. We found that the first factor predicted the strength of connectivity between brain regions known to be involved in the cognitive control of emotion, including the amygdala and the dorsolateral prefrontal cortex, whereas the second factor predicted the strength of connectivity between brain regions known to be involved in reward and attention, including the amygdala, the caudate and the thalamus. These findings suggest that individual differences in the ability to inhibit negative affect are mediated by prefrontal-limbic pathways, while the ability to be positive and use rewarding information is mediated by a network that includes the amygdala and thalamostriatal regions.

Effect of vitamin D supplementation on testosterone levels in men.

The male reproductive tract has been identified as a target tissue for vitamin D, and previous data suggest an association of 25-hydroxyvitamin D [25(OH)D] with testosterone levels in men. We therefore aimed to evaluate whether vitamin D supplementation influences testosterone levels in men. Healthy overweight men undergoing a weight reduction program who participated in a randomized controlled trial were analyzed for testosterone levels. The entire study included 200 nondiabetic subjects, of whom 165 participants (54 men) completed the trial. Participants received either 83 µg (3,332 IU) vitamin D daily for 1 year (n = 31) or placebo (n =2 3). Initial 25(OH)D concentrations were in the deficiency range (< 50 nmol/l) and testosterone values were at the lower end of the reference range (9.09-55.28 nmol/l for males aged 20-49 years) in both groups. Mean circulating 25(OH)D concentrations increased significantly by 53.5 nmol/l in the vitamin D group, but remained almost constant in the placebo group. Compared to baseline values, a significant increase in total testosterone levels (from 10.7 ± 3.9 nmol/l to 13.4 ± 4.7 nmol/l; p < 0.001), bioactive testosterone (from 5.21 ± 1.87 nmol/l to 6.25 ± 2.01 nmol/l; p = 0.001), and free testosterone levels (from 0.222 ± 0.080 nmol/l to 0.267 ± 0.087 nmol/l; p = 0.001) were observed in the vitamin D supplemented group. By contrast, there was no significant change in any testosterone measure in the placebo group. Our results suggest that vitamin D supplementation might increase testosterone levels. Further randomized controlled trials are warranted to confirm this hypothesis.

Resuscitating the heart but losing the brain: brain atrophy in the aftermath of cardiac arrest.

OBJECTIVES: Many survivors of cardiac arrest are left with considerable long-term impairments due to a transient ischemic state of the brain. Neuropsychologists identified a wide range of neuropsychological deficits in these patients besides the well-known amnesic syndrome. To date, there is no complete and unbiased documentation of the affected brain areas in vivo. We aimed to identify the brain tissue atrophy underlying the observed neuropsychological deficits in a case-control study. METHODS: We measured gray matter loss by voxel-based morphometry of 3-T structural magnetic resonance images in a sample of 12 patients who had had cardiac arrest with successful subsequent resuscitation in comparison with 12 individually age- and sex-matched control subjects. Such data are rare because many of these patients wear cardiac pacemakers. RESULTS: We found extensive reductions of gray matter volumes in the anterior, medial, and posterior cingulate cortex, the precuneus, the insular cortex, the posterior hippocampus, and the dorsomedial thalamus in tight correlation with neuropsychological impairments, namely, amnestic deficits and apathy. CONCLUSION: The identified neuroanatomical pattern of brain tissue loss substantiates the reports of wide-ranging neuropsychological impairments in patients after cardiac arrest.

Superficial siderosis of the central nervous system - treatment with steroids?

Steroids have been suggested as a therapeutic option for superficial siderosis of the central nervous system (SSCNS) without identifiable bleeding source. Longitudinal observational data of a patient with idiopathic SSCNS who was repeatedly treated with methylprednisolone over a course of 2 years are reported. The case history is critically discussed on the background of the sparse literature. In conclusion, if at all, there is only a limited and temporary, mostly subjective clinical response to steroids in SSCNS. Systematic studies of this medication in SSCNS do not seem warranted. Pathophysiological considerations hopefully may lead to more helpful medications for this chronic and debilitating disorder.

[A telemetrically-guided program for weight reduction in overweight subjects (the SMART study)]. / Telemedizinisch betreutes Programm zur Gewichtsreduktion bei Ubergewichtigen (SMART-Studie).

BACKGROUND AND OBJECTIVE: Compliance with weight reducing programs can be improved by intensive care and control. We tested a telemetrically-guided weight reduction program in overweight and obese persons. PATIENTS AND METHODS: 200 outpatients (62 males) with a mean body mass index of 34 kg/m (2) and a mean age of 47 years participated in a prospective study for one year. During the first six months, telemetrical support (weight-transmission via Bluetooth (short range)-technology, 20-minutes telephone consultation with a nutritionist) was given weekly. After six months, participants were randomly assigned either to a group with further telemonitoring support (telemetric group) or to a group without contact to our clinic (control group). At baseline, and after six and twelve months, body weight, body composition (bioelectrical impedance analysis), and parameters of the metabolic syndrome were assessed at our clinic. RESULTS: 16 participants terminated the study prematurely during the first 6 months and 19 participants (10 from the telemetric group and 9 from the control group) during the second 6 months. According to the intention-to-treat principle, mean weight loss was 6.7 kg (p < 0,001), mean loss of body fat was 5.1 kg (p < 0,001), and mean loss of fat-free mass was 1.6 kg (p < 0,001) within the first six months. Moreover, metabolic and cardiovascular risk markers such as waist circumference, blood pressure, serum triglycerides and blood glucose declined significantly (p < 0,001). Prevalence of the metabolic syndrome fell from 49.5% to 42.0 % (p < 0,05). During the second six months body fat content, waist circumference, and blood glucose increased again in the control group but not in the telemetric group (p < 0,05-0,001). CONCLUSION: The telemetrically-guided weight loss program was a more efficacious measure than the less intensive support without telemonitoring.

The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration.

The membrane redistribution and phosphorylation of focal adhesion kinase (FAK) have been reported to be important for cell migration. We previously showed that Lysophosphatidic acid (LPA) induced FAK membrane redistribution and autophosphorylation in ovarian cancer SK-OV3 cells and the signaling pathway consisting of Gi-Ras-MEKK1 mediated LPA-induced FAK membrane redistribution but not FAK autophosphorylation. We also showed that the disruption of the Gi-Ras-MEKK1 pathway led to a significant reduction in LPA-stimulated cell migration. These findings raised the question of whether LPA-induced FAK autophosphorylation was required for LPA-stimulated cell migration and what signaling mechanism was involved in LPA-induced FAK autophosphorylation. In this study, we expressed the membrane anchored wild-type FAK (CD2-FAK) in SK-OV3 cells and found that the expression of CD2-FAK greatly rescued LPA-stimulated cell migration in Gi or Ras-inhibited cells. However, Gi inhibitor pertussis toxin or dominant-negative H-Ras still significantly inhibited LPA-stimulated cell migration in cells expressing the membrane anchored FAK containing a mutation in the autophosphorylation site [CD2-FAK(Y397A)]. These results suggest that FAK autophosphorylation plays a role in LPA-stimulated cell migration. With the aid of p115RhoGEF-RGS, G12 and G13 minigenes to inhibit G12/13, we found that the G12/13 pathway was required for LPA-induced FAK autophosphorylation and efficient cell migration. Moreover, LPA activated RhoA and Rho kinase (ROCK) in a G12/13-dependent manner and their activities were required for LPA-induced FAK autophosphorylation. However, Rho or ROCK inhibitors displayed no effect on LPA-induced FAK membrane redistribution although they abolished LPA-induced cytoskeleton reorganization. Our studies show that the G12/13-RhoA-ROCK signaling pathway mediates LPA-induced FAK autophosphorylation and contributes to LPA-stimulated cell migration.

Emotion recognition in stroke patients with left and right hemispheric lesion: results with a new instrument-the FEEL Test.

The aim of this study was to investigate the effect of a stroke event on people's ability to recognize basic emotions. In particular, the hypothesis that right brain-damaged (RBD) patients would show less of emotion recognition ability compared with left brain-damaged (LBD) patients and healthy controls, was tested. To investigate this the FEEL Test (Facially Expressed Emotion Labeling) was used, a computer based psychometric test that assesses one's ability to recognize facially displayed basic emotions via a forced-choice paradigm. We examined 24 patients after a stroke event (13 RBD, 11 LBD) and compared them with a matched group of healthy controls (HC, n=29). Results showed that the stroke patients performed significantly worse in the FEEL Test than did HC (p<.001). This deficit was especially evident for negative emotions (fear, anger, sadness, and disgust). In contrast to other studies we did not find any significant differences between RBD and LBD patients in their ability to recognize emotions. These results indicate that a stroke event has a negative effect on the recognition of facially displayed emotions but suggest that this effect is apparently not dependent on the side of the brain damage.

Large sticky traps for capturing house flies and stable flies in dairy calf greenhouse facilities.

Large sticky traps were evaluated for stable fly, Stomoxys calcitrans (L.), and house fly, Musca domestica L., (Diptera: Muscidae) capture under field conditions in 5 dairy calf greenhouse facilities in New York. The farm with the highest stable fly capture had the highest house fly capture, and the farm with the lowest stable fly capture had the lowest house fly capture, suggesting that fly management practices greatly influenced trap captures. In general, stable fly populations, as reflected by increased trap capture, generally rose during the summer. Numbers of flies counted on calves did not increase, however, suggesting that the traps greatly reduced the potential stable fly pressure on the calves as the fly population increased. Estimated number of stable flies and house flies captured during this 10-wk study exceeded 142,000 and 900,000, respectively. Producers were generally pleased with the trap performance and most felt that these traps reduced flies in their calf greenhouses to acceptable levels.

The N400 reflects problems of thematic hierarchizing.

Using event-related potentials (ERPs), we present evidence that the current interpretation of the N400 component must be extended. This component is elicited in incorrect German sentences with two grammatical subjects, thereby showing its sensitivity to thematic relations between arguments in a sentence (who is doing what to whom). Such a violation only elicits an N400 when both arguments are animate but not when one of them is animate and the other inanimate, thus showing that the brain uses animacy information to overcome interpretation problems due to thematic competition. Structures with two subjects additionally elicit a P600 component which occurs independently of the animacy variation. Thus, animacy information does not appear to influence the syntactic processing problems resulting from such violations.